review article cellular and molecular connections between

Review ArticleCellular and Molecular Connections betweenAutophagy and Inflammation

Pierre Lapaquette12 Jean Guzzo12 Lionel Bretillon345 and Marie-Agnegraves Bringer345

1Universite Bourgogne Franche-Comte UMR PAM Equipe Vin Aliment Microbiologie Stress 21000 Dijon France2Agrosup Dijon UMR PAM Equipe Vin Aliment Microbiologie Stress 21000 Dijon France3INRA UMR1324 Centre des Sciences du Gout et de lrsquoAlimentation 21000 Dijon France4CNRS UMR6265 Centre des Sciences du Gout et de lrsquoAlimentation 21000 Dijon France5Universite Bourgogne Franche-Comte Centre des Sciences du Gout et de lrsquoAlimentation 21000 Dijon France

Correspondence should be addressed to Marie-Agnes Bringer marie-agnesbringerdijoninrafr

Received 15 March 2015 Revised 2 June 2015 Accepted 14 June 2015

Academic Editor Dmitri V Krysko

Copyright copy 2015 Pierre Lapaquette et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Autophagy is an intracellular catabolic pathway essential for the recycling of proteins and larger substrates such as aggregatesapoptotic corpses or long-lived and superfluous organelles whose accumulation could be toxic for cells Because of its uniquefeature to engulf part of cytoplasm in double-membrane cup-shaped structures which further fuses with lysosomes autophagy isalso involved in the elimination of host cell invaders and takes an active part of the innate and adaptive immune response Its pivotalrole in maintenance of the inflammatory balance makes dysfunctions of the autophagy process having important pathologicalconsequences Indeed defects in autophagy are associated with a wide range of human diseases including metabolic disorders(diabetes and obesity) inflammatory bowel disease (IBD) and cancer In this review we will focus on interrelations that existbetween inflammation and autophagyWewill discuss in particular howmediators of inflammation can regulate autophagy activityand conversely how autophagy shapes the inflammatory response Impact of genetic polymorphisms in autophagy-related geneon inflammatory bowel disease will be also discussed

1 Introduction

Autophagy is an evolutionarily conserved process Consti-tutive autophagy is required for cellular housekeeping (egelimination of damaged or long-lived organelles) [1] It is ahighly sensitive process that cells are induced in responseto a wide range of stressful conditions (physical chemicalor metabolic) in order to maintain cellular homeostasis [2]While the inflammatory responses are generally beneficialfor host protection this process needs to be spatially andtemporally tightly regulated to avoid a state of excessiveandor sustained inflammation that is potentially detrimen-tal Indeed prolonged exposure of tissues and organs tohigh concentration of inflammatory mediators representsa stressful environment for cells and can result in severedamage [3] Since an abnormal inflammation could disrupt

cellular homeostasis it is not thus surprising that autophagycontributes to damp inflammatory responses Autophagyacts by at least two means to protect cells from excessivelong lasting inflammation (i) indirectly by allowing efficientclearance of damaged organelles (mitochondria eg) orintracellular pathogenic microorganisms that both constitutepotent inflammatory stimuli and (ii) directly by suppressingproinflammatory complexes Naturally regulatory networksthat control autophagy activity are able to sense output signalsfrom various inflammatory mediators-associated signalingallowing a proper modulation of the process according toinflammation state In this review following a brief intro-duction on molecular mechanisms controlling autophagywe will make an overview of interrelations existing betweeninflammation and autophagy Facing tremendous numberof studies describing relationships between inflammatory

Hindawi Publishing CorporationMediators of InflammationVolume 2015 Article ID 398483 13 pageshttpdxdoiorg1011552015398483

2 Mediators of Inflammation

mediators and autophagy it is nearly impossible to becompletely exhaustive but we will highlight some of the best-characterized interactions between these two processes Inthe last part of the review we will discuss in more detailthe crosstalk between autophagy and inflammation duringpathophysiological situations especially inflammatory boweldiseases

2 Autophagy How Does It Work

21 Different Types of Autophagy Three main forms ofautophagy have been described in mammalians Macroau-tophagy corresponds to the sequestration of cytoplasmicstructures into double- or multimembrane vesicles termedautophagosomes Complete autophagosomes then transitalong microtubules to deliver their content to degradativecompartments lysosomes forming autolysosomes [1] Theterm microautophagy refers to the direct engulfment ofthe cytosolic material by invagination of the lysosomalmembrane [4] The third form of autophagy is chaperone-mediated autophagy (CMA) during which proteins contain-ing a pentapeptide motif (KFERQ-like sequence) are recog-nized by the cytosolic chaperone hsc70 (heat shock cognateprotein of 70 kDa) and its cochaperones that deliver themto the surface of lysosomes The substrate-chaperone com-plex binds to the lysosomal protein LAMP-2A (lysosome-associated membrane protein type 2A) and the substrateis unfolded Multimerization of LAMP-2A is required forsubstrate translocation inside the lysosome [5] In this reviewwe will focus only on macroautophagy (hereafter referredto as autophagy) and its interrelations with inflammatoryprocesses

Autophagy was first described as a nonselective bulkdegradation process sequestering a portion of the cytosoland used by the cell during nutrient deprivation periodIn light of studies during last decade it turns out thatautophagy can also be selective allowing under certainconditions the sequestration of specific substrates such asmitochondria (mitophagy) endoplasmic reticulum (ER- orreticulophagy) lipid droplets (lipophagy) peroxisomes (pex-ophagy) endosomes lysosomes secretory granules ribo-somes (ribophagy) cytoplasmic aggregates (aggregaphagy)inflammatory proteins and invading pathogens (xenophagy)[6] Structures targeted for destruction by autophagy areoften ubiquitinated A series of autophagy receptors termedSLRs for Sequestosome 1- (SQSTM1-) like receptors containubiquitin-binding domain (UBD) associated with a LIR(LC3-interacting region) motif and act as adaptors betweenK48- or K63-linked polyubiquitin chains on a targeted-substrate and ATG8 paralogs (LC3 GABARAP) bridgingautophagic cargoes to nascent autophagosomes [6]Membersof SLRs family include p62SQSTM1 NBR1 NDP52 andoptineurin Substrates can also be delivered to autophago-some in ubiquitin-independent manner as exemplified bymitophagy In some cases autophagy-mediated degradationofmitochondria relies on polyubiquitylation of proteins at theouter mitochondrial membrane and is dependent on PINK1(PTEN-induced putative kinase protein 1) and the E3 ligaseParkin In other cases however mitophagy is dependent on

mitochondrial outer-membrane proteins (eg NIX) that candirectly link mitochondria to autophagosomal membranesvia their own LIR domain Finally an alternative way hasbeen observed in neuronal cells and involves externalizationof an inner mitochondrial membrane phospholipid namedcardiolipin to the outer mitochondrial membrane and itsdirect recognition by LC3 [7 8]

22 Molecular Machinery of Autophagy Autophagy can bedivided into 6 main steps initiation vesicle nucleationelongation membrane elongation closure maturation anddegradation Initiation step leads to the formation of an isola-tionmembrane called phagophore most often in close vicin-ity with the endoplasmic reticulum (ER) Various organellesincluding the ER the Golgi apparatus mitochondria theplasma membrane and endosomes have been proposed toserve as membrane reservoir for phagophore generation andgrowth Initiation of autophagy requires two protein kinasescomplexes (i) the ULK12-ATG13-FIP200 complex whichis coupled with the autophagy suppressor TOR complex 1(mTORC1) and (ii) the Beclin1-Vps34-Vps15-ATG14 com-plex This last complex is usually inhibited by interactionswith proteins from the Golgi apparatus antiapoptotic Bcl2proteins and other signals transducers [9] Given the factthat autophagy is a highly dynamic process its activation islargely dependent on a set of posttranslational modificationssuch as phosphorylation acetylation and ubiquitylation [10]The mTORC1 complex consists of the mTOR kinase whichis a master cell-growth regulator integrating numerous intra-cellular and extracellular signals (growth factor nutrientsand cellular energy status) G120573L PRAS40 and raptor Underbasal condition the mTORC1 complex associates with theULK12-ATG13-FIP200 complex and phosphorylatesULK12and ATG13 resulting in the inhibition of ULK12 kinaseactivity Under stressful conditions (eg nutrient depriva-tion) AMPK activates ULK12 (in complex with ATG13and FIP200) directly by site-specific phosphorylation andindirectly by inhibiting mTORC1 [11] Dephosphorylationof mTOR-dependent inhibitory sites on the ULK12-ATG13-FIP200 complex releases ULK12 activity allowing autophos-phorylation of this complex and its interaction to theATG101 protein in an ATG13-dependent manner [12] Theseevents lead to the subsequent recruitment and activation ofthe Beclin1-ATG14-Vps34-Vps15 complex at the membraneinducing nascent phagophore formation This vesicle nucle-ation step relies on dynamic assembly of both autophagyinitiation complexes (ULK12-ATG13-ATG101-FIP200 andBeclin1-ATG14-Vps34-Vps15) on the exocyst a scaffoldingprotein complex involving the Ras-like small G-protein RalBand its effector Exo84 which acts as an activation platformfor core autophagy machinery [13] The Beclin1-associatedphosphatidylinositol 3-kinase class III Vps34 marks the sitewhere the phagophore emerges from the ER by generating aPI3P-enriched structure called omegasome This event leadsto the recruitment of PI3P-binding proteins such as DFCP1(double FYVE-containing protein 1) Alfy and WIPI (WD-repeat domain phosphoinositide interacting) family proteinsMembers of the WIPI family WIPI1 WIPI2 and WIPI4recognize PI3P accumulation at the nascent autophagosome

Mediators of Inflammation 3

and are necessary for the recruitment of the autophagosomeelongation complex ATG12ndashATG5ndashATG16L1 complex [14]

Elongation of the phagophore membrane involves twoubiquitin-like proteins ATG12 and ATG8 Similarly to ubiq-uitination ATG12 is conjugated to ATG5 (substrate) byATG7 (E1-like enzyme) protein andATG10 (E2-like enzyme)Then the ATG5-ATG12 complex can interact noncova-lently with ATG16L1 and associates with the phagophoreThe second ubiquitin-like reaction involves ATG7 (E1-like enzyme) and ATG3 (E2-like enzyme) enzymes andis required for conjugation of ubiquitin-like moleculesof the ATG8 family (LC3 GABARAP and GATE-16) tothe lipid phosphatidylethanolamineWhereas ATG5-ATG12-ATG16L1 complex will dissociate from closed autophago-somes LC3-II the lipidated form of LC3 remains associatedwith the autophagosome until fusion with the lysosome[15] It has been observed that ATG5-ATG12-ATG16L1-positiveLC3-negative pre-autophagosomal structures coa-lesce through SNARE-mediated homotypic fusions therebyincreasing the size of the membrane constituting thephagophore a prerequisite for optimal acquisition of LC3 andprogression from autophagosome precursor to phagophore[16] Although its function is not still fully understood thetransmembrane protein ATG9 is also proposed to orchestratemembrane delivery to the phagophore assembly site [17]

Closure of autophagosome is thought to require LC3-conjugation system [18] However the lack of mutant cellsdefective for this step does not allow for precise molec-ular insights Once edges of the phagophore are sealedsequestering substrates to be degraded the autophagosomemigrates along microtubules to a perinuclear location andinteracts with endosomes and lysosomes [19] Fusion of theseorganelles is orchestrated by SNARE proteins (VAMP3 andVAMP7) and Rab GTPases (at least Rab7 and Rab11) [20ndash22] The Beclin1 protein which is essential for autophagyinitiation also plays a role in autophagosomal maturationby indirectly modulating Rab7 protein activity [22] The laststage of autophagy is the efflux into the cytosol of metabo-lites (amino acids sugars and lipids) that are generatedby autolysosomal degradation It involves transmembraneproteins termed permeases In yeast recycling of amino acidsfrom autophagosomes involves three vacuolar amino acidpermeases Atg22 Avt3 and Avt4 [23] Interestingly mTORwhich is the master suppressor of autophagy is reactivatedupon autophagy termination by amino acids release andstimulates extrusion of lysosome-derived membranes fromautolysosomes to form new functional lysosomes [24]

3 Mediators of InflammationRegulating Autophagy

31 Innate Immune Receptors At the cellular level presenceof pathogens is detected by ldquopattern recognition receptorsrdquo(PRRs) located at the plasma membrane (Toll-like receptors(TLRs) 1 2 4 5 and 6) at endosomal membranes (TLR3TLR7 TLR8 and TLR9) or in the cytosol (Nod-like receptors(NLRs) retinoic acid-inducible gene-I- (RIG-I-) like recep-tors (RLRs) C-type lectin like receptors (CLRs)) [25ndash28]These innate immune receptors recognize highly conserved

structural motifs present on microbes termed ldquopathogen-associatedmolecular patternsrdquo (PAMPs) such as the bacterialcell wall components lipopolysaccharide (LPS) flagellinand lipoproteins bacterial and viral nucleic acids and thefungal cell wall components zymosan andmannanThey alsodetect ldquodanger-associated molecular patternsrdquo (DAMPs) thatsignalize host cellular damage Connections exist betweenautophagy and innate immune receptors where PRRs serveas sensor for microbial presence and autophagy ensures theirintracellular elimination through lysosomal degradation It isimportant to notice that PRRs repertoire varies substantiallyfrom one cell type to another thus by contrast to starvation-induced autophagy PRRs-mediated autophagy will be morecell type dependent In addition PRRs distribution could beinfluenced by cell polarity For example in the colon TLR5is only exposed on the basolateral side of enterocytes and isabsent from apical side [29]

Screening of PAMPs library for their effects on autophagyshowed that prototype ligands of various TLRs includ-ing TLR1 TLR3 TLR4 TLR5 TLR6 and TLR7 induceautophagy inmouse and humanmacrophages [30 31] TLR9-dependent induction of autophagy has also been reported inhuman colonic epithelial cells stimulated by bacterial CpGmotifs [32] Invading pathogens such as Listeria monocyto-genes (Lmonocytogenes) and Staphylococcus aureus have alsobeen shown to activate autophagy inmacrophages in a TLR2-dependent manner and thereby triggered their own elimina-tion [33 34] Interestingly activation of autophagy throughTLR stimulation by agonists enables also the elimination ofnoncognate intracellular pathogens [30]

Connections between TLR and autophagy are complexto study since various downstream signaling effectors areengaged according to the innate immune receptor activatedData discrepancies exist regarding the adaptor (Myd88 versusTRIF) involved in autophagy induction by TLR4 stimulationinmacrophages [31 35] Delgado et al showed that activationof autophagy via TLR7 upon macrophages stimulation withssRNA is dependent on MyD88 [30] Mechanistically con-nection betweenTLR-signaling and autophagy is supposed tobe mediated by the adaptor proteins TRIF or Myd88 that arefound to coimmunoprecipitate with Beclin1 and reduce thebinding of Beclin1 to the inhibitory protein Bcl2 leading toautophagy activation [31] Physical association ofMyd88withmTOR has also been reported allowing activation of mastertranscription factors (interferon-regulatory factor- (IRF-) 5and IRF-7) for proinflammatory cytokine- and type I IFN-genes [36] In addition mycobacterial infection of humanmacrophages and zebrafish embryos induced DRAM1 (DNAdamage-regulated autophagymodulator 1)mediated selectiveautophagy in a Myd88 and NF-120581B-dependent manner [37]

Nod receptors stimulation by bacterial peptidoglycancomponents induces autophagy and results in enhanced bac-terial killing and antigen presentation [38 39]Themolecularinteraction between the cytoplasmic Nod1 and Nod2 recep-tors and autophagy has beennicely shed in light byD Philpottgroup They showed that ATG16L1 interacts with Nod recep-tor that enables recruitment of autophagy machinery at thebacterial entry site and the subsequent delivery of bacteriainto autophagosomes for degradation [39] ldquoNODophagyrdquo


entails other autophagy-related proteins such asATG5ATG7and receptor-interacting serine-threonine kinase-2 (RIPK-2) [38] Autophagy regulation by Nod proteins is evolu-tionarily conserved since the drosophila homologue PGRP-LE recognizing also peptidoglycan fragments is able toinduce autophagy upon L monocytogenes challenge [40]Modulation of autophagy by other NLR family membersinvolved in inflammasomes assembly has been reported [41ndash43] Activation of AIM2- or NLRP3-mediated inflamma-somes triggers the activation of the small G protein RalB andautophagosome formation [43] Through binding to Exo84RalB induces the assembly of catalytically active ULK1 andBeclin1-Vps34 complexes [13] Flagellin recognition by theNLR proteins Naip5 and NLRC4 stimulates autophagosometurnover [41]

Conversely NLRs can negatively regulate autophagyNLRC4 and NLRP4 negatively regulate autophagic processesthrough an association with Beclin1 In addition NLRP4physically interacts with the C-VPS complex (VPS11 VPS16VPS18 and Rab7) that controls membrane tethering andfusion of vacuolar membranes thereby blocking maturationof autophagosomes to autolysosomes [44]

To summarize PRRs by sensing various microbial prod-ucts from bacteria virus and fungi are able to modulateautophagy at multiple steps (initiation and maturation)

32 Cytokines By binding to their specific receptors locatedat the cytoplasmic membrane cytokines modulate auto-phagy In a general way Th1 cytokines (IL-2 TNF-120572 andIFN-120574) are considered as autophagy inducers whereas Th2cytokines (IL-4 IL-5 IL-6 IL-10 and IL-13) and anti-inflammatory cytokines are regarded as autophagy repressors[45] Cytokines that have been reported to induce autophagyencompass IL-1 IL-2 IL-6 TNF-120572 TGF-120573 and IFN-120574 [45]

Autophagy induction by cytokines may constitutean important mechanism in the elimination of invasivepathogens IFN-120574 illustrates this mechanism since it pro-motes degradation of intracellular Mycobacterium tubercu-losis and Chlamydia trachomatis by inducing autophagy [4647] Induction of autophagy by IFN-120574 involves immunity-related GTPase such as murine Irgm1 human IRGM Irga6andmembers of the 65-kDa guanylate binding protein family[46ndash49] Of note unlike the Irgm1 gene in mice the humanIrgm1 ortholog IRGM is not responsive to IFN-120574 but inter-estingly it remains able to induce autophagy upon infection inepithelial cells and macrophages [49ndash51] A single nucleotidepolymorphism (SNP) in IRGM (261T) is associated withresistance toM tuberculosis infection in people carrying thisprotective variant [52] In Irgm1minusminus macrophages an alter-native activation pathway of autophagy by IFN-120574 dependingon the p38 MAPK has been described [53] In human hepa-tocellular carcinoma cells IFN-120574 induces autophagy throughIRF-1 signaling pathway and this autophagy activation isassociated with cell death [54] Induction of autophagy bytype I IFNs has also been reported in several cancer celllines and involved JAKSTAT and PI3K-mTOR pathways[55] Type I IFN proteins include the IFN-120572 subtypes IFN-120573and IFN-120596 and play pleiotropic functions such as antiviralantiproliferative and immunomodulatory activities

The proinflammatory cytokine and death ligand TNF-120572represents also an autophagy inducer in various cell typesincluding T-lymphoblastic leukaemic cells osteoclasts orEwing sarcoma cells [56ndash58] TNF-120572 regulation of autophagyhas been shown to be dependent on various signaling path-ways including JNK and Erk signaling and via the productionof reactive oxygen species (ROS) [59ndash62] The role of TNF-120572in autophagy is also supported by studies onM tuberculosissince reactivation of tuberculosis associated with anti-TNF-120572 treatments (infliximab adalimumab certolizumab pegoland etanercept) is suspected to at least partially depend onsuppression of the antibacterial autophagic process [63 64]

Various effects on autophagy have been reported for IL-6depending on considered tissue IL-6 enhanced autophagicactivity in myeloid cells and mouse pancreatic tumor cells[65 66] In contrast IL-6 overexpression blocks autophagyin human bronchial epithelial cells by supporting interactionbetween Beclin1 and the antiapoptotic Bcl2 protein Mcl-1[67] Other cytokines that have been described to induceautophagy include IL-1120573 which is suspected to be an endoge-nous inhibitor of the mTOR pathway [68] and TGF-120573 whichstimulates autophagy through various signaling pathwayssuch as JNK Smad and TAK1 pathways [69 70]

Conversely some Th2 and anti-inflammatory cytokinesexert autophagy-suppressive functions Regarding IL-4 andIL-13 cytokines they inhibit starvation-induced autophagythrough stimulation of PI3KAkt signaling pathway and areable to counteract IFN-120574-induced autophagy in a signal trans-ducer and activator of transcription 6 (STAT6) dependentmanner [71] The anti-inflammatory cytokine IL-10 has alsobeen described to inhibit starvation-induced autophagy bystimulating the PI3KAkt signaling pathway [72]

33 Reactive Oxygen Species Several lines of evidence indi-cate that reactive oxygen species (ROS) are early autophagyinducers upon nutrient deprivation This is supported bydata showing that treatment with antioxidants partially orcompletely reverses the process [73] Under nutrient depri-vation it has been reported as the expulsion of reducedglutathiones (GSH) which are powerful antioxidants bythe plasma membrane translocator ABCC1MRP1 (multidrugresistance protein 1) in the extracellular milieu [74] Thisresults in a shift of the intracellular redox state toward oxi-dizing conditions and may favor oxidation of redox-sensitiveproteins inducing consequently the early autophagy Mito-chondria represent the principal source of ROS that triggersautophagy It is postulated that superoxides and hydro-gen peroxide the main ROS produced by mitochondriaupon nutrient deprivation could activate autophagy by atleast two ways One molecular mechanism that has beendescribed is the activation of the AMPK (51015840-adenosinemonophosphate-activated protein kinase) an energy sensorof the cell through S-glutathionylation of its cysteines S-glutathionylation is a posttranslational modification of cys-teines frequently induced in cells as a response to ROSproduction AMPK stimulates autophagy by phosphorylat-ing TSC2 (tuberous sclerosis complex 2) an inhibitor ofmTORC1 raptor a component of the mTORC1 complex andby phospho-activatingULK1 [11 75 76] Anothermechanism


by which ROS induce autophagy is by oxidizing a cysteineresidue near the catalytic site of the cysteine protease ATG4thereby stimulating its proteolytic activity and enhancingautophagy [77 78]

34 Inflammation-RelatedTranscription Factors Until recentlytranscription control of autophagy was clearly underappre-ciated but compelling evidences during last years demon-strate that a network of transcription factors is involved infine-tuning of autophagy Some transcription factors (TFs)which orchestrate inflammatory responses have been alsodescribed as transcriptional regulators of the core autophagygenes A prototypical example of these TFs is the nuclearfactor-120581B (NF-120581B) p65RelA family member which hasbeen shown to upregulate BECN1 and SQSTM1 transcription[79 80] Other inflammation-related TFs that are able tomodulate autophagy genes transcription include hypoxiainducible factor-1 (HIF-1) JUN signal transducers andactivators of transcription (STAT) 1 and STAT3 [81] HIF-1stimulates autophagy by enhancing transcription of BNIP3(BCL2adenovirus E1B 19 kDa protein-interacting protein 3)and BNIP3L (BNIP3-like) encoding genes [82] These twoproteins which belong to the BH3-only Bcl2 family proteinsare known to activate autophagy C-JUN is recruited to theBeclin1 and ATG8 genes promoter regions in response toceramide treatment and thereby enhances transcription ofthese genes [83 84] A role as negative autophagy regu-lators has been described for STAT1 and STAT3 since animpaired expression of those TFs correlates with an increasedautophagy activity and stimulates transcription of some Atggenes including Atg12 and Beclin1 [85 86] TFs belonging tothe nuclear receptors family such as peroxisome proliferator-activated receptor 120572 (PPAR120572) PPAR120574 and Farnesoid X-activated receptor (FXR) which function as ligand-activatedTFs andmodulate inflammatory response can alsomodulateautophagy [87 88] PPAR120572 and FXR have opposite effecton autophagic genes transcription since pharmacologicalactivation of PPAR120572 leads to an upregulation of the expres-sion of autophagy genes whereas FXR activation leads toa repression Copetti and colleagues demonstrate that thesetwo nuclear receptors compete for binding to the same siteon autophagy genes promoters [79] Inflammatory state hasalso been described to modulate the activity of transcriptionfactor EB (TFEB) a master regulator that orchestrates theexpression of autophagy and lysosomal genes [89] HenceTFs represent an additional complex layer of regulationthereby inflammation deeply affects autophagy-associatedtranscriptional program

4 Regulation of Inflammation by Autophagy

41 Regulation of Inflammasomes Inflammasomes are intra-cellular signaling platforms that detect a set of substancesemerging during infections tissue damage or metabolicimbalances and that proteolytically activate the highly proin-flammatory cytokines IL-1120573 and IL-18 [90]Thesemultimericprotein complexes usually consist of three partners aninflammasome sensor protein which can be a PAMP- orDAMP-detecting module in the form of a NLR such as

NLRP3 and NLRC4 or an endogenous DNA (released frommitochondria) detecting module such as AIM2 (absent inmelanoma 2) the adaptor protein ASC and caspase-1 thatenzymatically processes pro-IL-1120573 and pro-IL-18 for theiractivation Activation of inflammasomes also causes pyropto-sis which corresponds to a rapid and proinflammatory formof cell death [90]

Autophagy acts as a negative regulator of inflammasomesMice those are deficient in ATG16L1 which is essentialfor autophagy present higher IL-1120573 and IL-18 levels insera in response to LPS stimulation or during colitis [91]These results have been confirmed by pharmacological (3-methyladenine treatment) or genetical (LC3B and Beclin1)inhibitions of autophagy that all result in higher IL1-120573 production upon PAMPs stimulation [43 92] At theopposite TLR- or rapamycin-induced autophagy leads toreduced amount of pro-IL1-120573 [93] However the molecularmechanisms by which autophagy regulates inflammasomeactivation are not yet fully understood Autophagy couldact directly by sequestering and degrading ubiquitinated-inflammasomes and pro-IL-1120573 molecules or indirectly bylowering endogenous sources inducing inflammasome for-mation such as mitochondrial ROS and DNA [43 92ndash94]

42 p62SQSTM1 as a Regulator of the Oxidative StressResponse In addition to its role in clearance of polyubiquiti-nated proteins and bacteria by autophagy [95 96] and in theregulation of the nutrient-sensing pathway [97] p62SQTM1is also involved in the regulation of inflammatory medi-ators production The p62SQTM1 protein can induce theupregulation of oxidative stress response genes particularlythose controlled by Nrf2 an antioxidant transcription factorUnder basal condition Nfr2 is sequestered in the cytoplasmby Keap1 Upon oxidative stress p62SQSTM1 interacts andcompetes with the Nrf2-binding site on Keap1 leading tothe stabilization and the nuclear translocation of Nrf2 andtranscription of target genes including key ROS scavengersencoding genes [98] Thus the Nrf2 activation is reinforcedby degradation of p62SQSTM1-Keap1 complex by autophagyand through the activation of p62SQSTM1 transcription byNrf2

43 Secretion of Mediators of Inflammation Besides theconventional secretion process by which proteins endowedwith a leader peptide undergo modification in the ERtransit through the Golgi apparatus and are secreted uponfusion of post-Golgi carriers with the plasma membranean unconventional secretion process based on autophagyhas been described This secretion process first describedin yeast is involved in the secretion of proteins devoid ofleader peptide It is present in mammalian cells and termedldquosecretory autophagyrdquo (also referred to as ldquoautosecretionrdquo [99]or ldquotype III secretionrdquo [100]) The principal features definingsecretory autophagy are the involvement of ATG proteinsand autophagy process and dependence onGolgi reassemblyand stacking protein GRASP55 and GRASP65The secretoryautophagy is a rising investigation area and a number ofpoints remain to be elucidated to understand how autophagyorients peptide to secretion or simple degradation It has


been reported in mammalian cells that secretory autophagycontributes to the secretion of proinflammatory cytokines(IL-1120573 and IL-18) and alarmins (high mobility group box(HMGB)-1) under transient and specific circumstances [101]This process depends on ATG5 inflammasome GRASP55and Rab8a

44 Control of Macrophages Polarization Mononuclear pha-gocytes and among them macrophages play a central rolein the orchestration and expression of innate and adaptiveimmune responses One of the hallmarks of these cells is theirhigh diversity and plasticity In tissues in response to a largevariety of environmental cues (eg growth factors cytokinesmicrobial products or glucocorticoids)mononuclear phago-cytes undergo transcriptional reprograming that shape theirphenotype and functions M1 (classical) and M2 (alter-native) phenotypes being the extremities of a continuumof activation states [102] Macrophage differentiation frommyeloid lineage relies on sustained expression of the tran-scription factor PU1 Then depending on the macrophagemicroenvironment M1 macrophage polarization is mediatedby STAT1 and IRF-5 whereas M2 polarization is supportedby STAT6 IRF-4 and PPAR120574 [103] Multiple other signal-ing molecules transcription factors epigenetic mechanismsand posttranscriptional regulators involved in fine-tuningof macrophage polarization have been characterized [104]Of note macrophage polarization has been shown to bea transient and reversible state [105] Schematically M1macrophages stimulate a proinflammatory response againstintracellular microorganisms and tumors cells whereas M2macrophages are immunosuppressive cells and participatein cancer progression by supporting key processes such asangiogenesis tissue repair and remodeling

In addition to playing role in macrophages migrationand differentiation which will not be discussed in thisreview evidences showed that autophagy is involved in thecontrol of macrophage polarization Binding of hepatoma-derived factors to TLR2 stimulate M2 macrophage polar-ization a phenotype expressed by most of tumor-associatedmacrophages (TAM) from established tumors by regulat-ing cytoplasmic NF-120581B level through selective autophagy[106 107] Pharmacological treatment with bafilomycin A1a lysosomal inhibitor or genetic defects (knockdown ofATG5) that impaired autophagy prevents degradation ofNF-120581B (p65) and forces the M2 macrophages to secretehigh levels of inflammatory cytokines which characterizedM1 phenotype In addition the mTOR pathway has beendescribed as a critical element of themonocyte differentiationto TAM Inhibition of mTOR through rapamycin treatmentcaused themonocytes to differentiate toward aM1phenotypewhereas activation of mTOR by RNA interference-mediatedknockdown of the mTOR repressor TSC2 induced the differ-entiation of monocytes toward a M2 macrophage phenotype[108] A defect inCatS a cathepsinwhose expression is upreg-ulated in several tumors is associated with accumulation ofautophagosomes and attenuation of the autophagic flux inmacrophages It has been recently demonstrated that Cat S-mediated autophagic flux is required tomaintain polarizationof the M2 TAMs phenotype [109]

5 Autophagy in Human InflammatoryDiseases the Example of Crohnrsquos Disease

Given the multiple roles played by autophagy in immunehomeostasis malfunctions of this process have been associ-ated with the pathogenesis of a variety of diseases Henceautophagymay impact on the onset or progression of varioushuman diseases associated with a chronic inflammatorystate including inflammatory bowel diseases (IBDs) Pagetrsquosdisease infectious diseases (tuberculosis) lysosomal stor-age disorders and autoimmune disorders (systemic lupuserythematosus rheumatoid arthritis multiple sclerosis andtype 1 diabetes) [110] Among them IBDs are the moststudied inflammatory diseases for their link with autophagyalteration and especially Crohnrsquos disease (CD) CD andulcerative colitis (UC) represent the two major forms ofidiopathic IBD It is now widely accepted that the etiologyof IBD involves environmental and genetic factors that leadto dysfunction of the epithelial barrier with consequentderegulation of the mucosal immune system and responsesto gut microbiota [111] Human genetic studies over the lastdecade and experimental studies have revealed the keystonerole played by autophagy in the disorders associated with CD

51 Autophagy Genes as Risk Factors for Crohnrsquos Disease Theinitial identification of the link between autophagy and CDarose from genome-wide association studies (GWAS) whichrevealed the association between a coding single nucleotidepolymorphism (SNP) in the ATG16L1 gene of the autophagycore machinery and an increase risk of CD onset [112] Twoothers genes associated with autophagy have been confirmedas CD susceptibility genes Irgm (immunity-related GTPasefamilyM) and LRRK2 (leucine-rich repeat kinase 2) [113 114]More recently whole exome sequencing of CD patients hasidentified a CD-associated missense variant (V248A) in theautophagy receptor NDP52 [115] CD-associated polymor-phisms in ATG16L1 and IRGM encoding genes have beenreliably found in many patient cohorts as reported by a meta-analysis [116 117] Of note Irgm polymorphisms are alsoassociated with an increased risk in developing UC what isnot true for other autophagy-related genes associated withCD-susceptibility [116]

Regarding Irgm a synonymous variant within the codingregion (rs10065172 CTG gt TTG leucine) was initially linkedto CD [114] and this silent polymorphism was found to be inperfect linkage disequilibriumwith a 20 kb deletion upstreamof Irgm [118] Results showed that the 20 kb deletion does notimpair in a reliable manner expression of the IRGMmRNAbut that silent polymorphism alters the recognition of theIRGMmRNA by a family of microRNA (miR) miR-196a andmiR-196b [51 118] In a specific study to identify rare SNPsin autophagy-related genes a CD-associated SNP in the Ulk1gene locus has been identified but the functional relevanceof this genetic variation in the disease is still unknown[119] Association between granulomas one of the micro-scopic hallmarks of CD and variants in autophagy ATG4AATG2A Fnbp1l and ATG4D genes has also been reported[120] In addition three mutations in Nod2 including aframeshift mutation (L1007fsinsC) that results in a truncated


NOD2 protein and two amino acid substitutions (R702Wand G908R) have been reported to be strongly associatedwith CD onset [121 122] Mutations in Nod2 encoding geneimpaired ability of this innate immune receptor to interactwith ATG16L1 and recruit the autophagy machinery fordegradation of invasive bacteria [39] ATG16L1 indepen-dently of its role in autophagy acts as a negative regulatorof the Nod1 and Nod2-mediated proinflammatory signalingpathways by negatively regulating the activation of the Rip2kinase [123]These studies strengthen the connection existingbetween Nod2 the first gene historically associated withCDetiology and autophagy-related-genes associated recentlywithCDbyGWAS highlighting the importance of autophagyin CD onset

52 Endoplasmic Reticulum Stress Related Inflammation ERstress is caused by the accumulation of unfolded ormisfoldedproteins in the ER Cells secreting large amounts of proteinsuch as Paneth cells and Goblet cells in the intestine arehighly susceptible to ER stress for survival and to executingtheir secretory functions The unfolded protein response(UPR) enables the cell to resolve the ER stress by facilitatingthe folding export and degradation of proteins accumulatingin the ER during stressed conditions Three ER membraneresident proteins IRE1 (inositol requiring transmembranekinase endonuclease 1) PERK (pancreatic ER kinase) andATF6 (activated transcription factor 6) sense the presence ofunfolded protein in the ER lumen and induce a transcrip-tional program necessary for the UPR In the absence ofmisfolded proteins in the ER lumen IRE1 PERK and ATF6are maintained as inactive complexes through associationwith Grp78 [124]

Complex connections exist betweenER stress and inflam-mation In mice genetic deletion of molecules involved inthe UPR such as IRE1120573 the transactivator of UPRrsquos Xbp1(X-box binding protein 1) and Agr2 (Anterior gradient 2)target genes which is a member of the ER protein disulfideisomerase (PDI) gene family are associated with either spon-taneous intestinal inflammation andor increased sensitivityto the experimental induction of colitis [125ndash127]

In human genetic studies have identified theUPR-relatedgenes Xbp1 and ORMDL3 (orosomucoid-like 3) which isinvolved in ER calcium homeostasis as risk loci associatedwith Crohnrsquos disease [113] Evidences for increased ER stressresponse in patients with CD include an increased expressionof Grp78 and an increasedXbp1 splicing in the small intestineand colon of CD patients comparatively to controls [125 128129]

Intestinal epithelial cell-specific deletion ofXpb1 (1198831198871199011ΔIEC)andmost notably in Paneth cells leads to autophagy inductionlinked to ER stress related PERK-eIF2120572 signaling pathway[130] Interestingly spontaneous ileitis observed in1198831198871199011ΔIECmice is converted into severe CD-like transmural ileitis whenbothmechanisms ER stress and autophagy are compromised(Atg71198831198871199011ΔIEC and Atg16L11198831198871199011ΔIEC double transgenicmice) [130] In addition ATG16L1-dependent autophagyrestrains IRE1120572-mediated NF-120581B activationThus autophagymay function as a buffer mechanism in intestinal epithelial

cells protecting cells from inflammation generated uponsustained ER stress

Evidences showed that the crosstalk between UPR andautophagy may be bidirectional Defective autophagy pro-motes ER stress in hepatocytes [131] and increased Xbp1splicing and Grp78 expression have been observed in119860119905119892161198711ΔIEC mice crypt compartment compared to wild-type [130] In addition patients with CD carrying the119860119879119866161198711T300A risk variant frequently exhibit ER stress intheir Paneth cells in contrast to those harboring the normalvariant [132]

53 Inflammation Related to Impaired Xenophagy Theterm ldquoxenophagyrdquo refers to the control of intracellularpathogens by autophagy Invasive bacteria that escape intothe cytosol such as Shigella flexneri or Listeria monocyto-genes or those that reside in intracellular vacuoles suchas Salmonella Typhimurium or Mycobacterium tuberculosiscan be entrapped into autophagosomes and delivered tolysosomes for degradation Keymolecules that target bacteriafor xenophagic degradation had been identified and includeNLRs (NOD1 and NOD2) ubiquitin galectins and diacyl-glycerol (DAG) [96] Recent evidences show that cell infec-tion with pathogens such as S flexneri or S Typhimuriumtriggers an amino acid starvation response an inhibitionof the mTOR signaling and thereby induces autophagy[133] This suggests that xenophagy response against inva-sive pathogens might derive from primordial metabolicstress response reinforcing the link existing between cellmetabolism and immune cellular defense

Dysbiosis of the fecal- lumenal- andmucosal-associatedmicrobiota have been described in CD patients [134] andsubstantial evidence supports an abnormal colonization ofthe mucosa and lesions of patients with ileal form of CDby Escherichia coli belonging to the pathovar designatedadherent-invasive E coli (AIEC) [135 136] One putativeconsequence of impaired autophagy is an uncontrolledpathobionts overgrowth due to defective intracellular bac-terial clearance ldquoPathobiontrdquo term refers to microorgan-isms that are usually recognized as harmless but that canbecome pathogens under certain environmental conditions(eg host detrimental diet or host genetic susceptibility)Such a hypothesis is supported by data demonstrating thatinflamed tissues of the terminal ileum of CD patients withthe risk allele of ATG16L1 harbor a higher abundance ofthree pathosymbiont groups Enterobacteriaceae (mostly Ecoli) Bacteroidaceae (mostly Bacteroides fragilis group) andFusobacteriaceae in comparison with those with the pro-tective allele [137] It has been shown that autophagy pro-tects against dissemination of pathobionts and true invasiveintestinal pathogens since intestinal epithelial cell-specificdeletion of Atg5 exhibits increased dissemination of thesebacteria to extraintestinal sites [138] Silencing expression ofATG16L1 by siRNA in human macrophages and epithelialcells and expression of the risk variant of ATG16L1 byepithelial cells impair AIEC handling by autophagy and favortheir persistence within host cells [139 140] Monocytes fromCD patients homozygous for the ATG16L1 risk allele showed


Autophagy

Proinflammatorysignaling complexes

Invasive microorganisms

Damaged organelles

Elimination of

Infla

mm

atio

nIn

flam

mat

ion

TLRs

NLRs

PAMPs(bacterialviralfungal)

Cytokines and chemokines

IL-2

IL-1

IL-6

ROS

Atg genes

HIF1

STAT1STAT3

Jun

FXR

PPAR120574PPAR120572TFEB

Inflammation-related TFs

Damaged mitochondria

TNF-120572 IFN-120574

TGF-120573

NF-120581BNF-120581B

Figure 1 Autophagy and inflammation By integrating output signals from PRRs (brown box) cytokines and chemokines (blue box) andROS (orange box) autophagy regulatory network is able to dynamically respond to inflammation Transcriptionally inflammation-relatedtranscription factors shape transcriptional program of autophagy (grey box) Active autophagy reduces inflammation at least by mediatingdamaged organelles clearance lowering microorganisms intracellular load and degrading inflammatory mediators (red box)

impaired killing of AIEC under inflammatory conditionscomparedwith those homozygous for theATG16L1 protectiveallele [137] Similarly impaired xenophagy against AIECbacteria has been described in dendritic cells isolated fromdonors with CD-associated Nod2 variants and in peritonealmacrophages isolated from Nod2 knockout mice [38 139]Conversely pharmacological and physiological induction ofautophagy overcomes defects in intracellular AIEC clearanceSimilarly to ATG16L1 and Nod2 decreased expression levelof IRGM totally impairs autophagy initiation and leads touncontrolled replication of AIEC bacteria An unexpectedresult was that overexpression of IRGM as observed in theintestinal mucosa of CD patients (compared to controls)also altered the autophagosome maturation step supportingintracellular AIEC persistence [51]

Risk polymorphisms associated to CD in the autophagy-related Nod2 ATG16L1 and Irgm genes are associatedwith aberrant inflammatory responses Defects in autophagycaused by alteration of the expression of autophagy-relatedgenes lead to an exacerbated inflammatory response inhuman THP-1 macrophages [139] Surprisingly in a mousemodel of ATG16L1 deficiency this abnormal higher inflam-matory response has been shown to confer protectionagainst uropathogenic E coli (UPEC) infection by allow-ing an accelerated clearance of these bacteria in an IL-1120573-dependent manner [141 142] At the opposite forced

induction of autophagy decreased proinflammatory cytokinerelease Recently it has been shown that AIEC infectionupregulated levels of microRNAs like miR-30c and miR-130ain intestinal epithelial cells by activating NF-120581B [143] Upreg-ulation of these microRNAs inhibited autophagy by reducingthe levels of ATG5 and ATG16L1 and led to increasednumbers of intracellularAIECand exacerbated inflammatoryresponse In vitro blocking of miR-30c and miR-130a inAIEC-infected cells restored functional autophagy Interest-ingly ileal samples from patients with CD have increasedlevels of these same microRNAs and reduced levels of ATG5and ATG16L1 [143]

6 Conclusion

As illustrated by studies detailed above in this reviewautophagy and autophagy-related proteins are essential com-ponentsmodulating inflammatory response either directly byacting on stability or secretion of inflammatory mediators orindirectly by suppressing intracellular stressors (eg dam-aged organelles intracellular pathogenic microorganismsand ER stress) Autophagy regulatory network integrates awide range of signals from innate immune receptors sensingPAMPs (TLRs and NLRs) cytokines and ROS and therebyis able to respond appropriately according to the degree ofinflammatory state (Figure 1)


Autophagy has a significant impact on health since ithas been shown that specific induction of autophagy canincrease lifespan in multiple animal species [144] We couldassume that the ability of autophagy to restrain detrimentalside effects of inflammation might contribute to its posi-tive role on health An interesting parallel supporting thishypothesis is the fact that during aging there is a decreasein autophagy efficiency [145] concomitantly to an increase inthe basal inflammation level [146] Novel therapies designedto enhance autophagy might represent an attractive strategyto overcome autophagy insufficiencies associated with somehuman inflammatory diseases such as CD Beyond thewell-known autophagy inducer rapamycin already used inclinic as an immunosuppressive and antitumor drug [147]high-throughput screening studies have identified additionalmolecules already FDA approved that are able to modulatethe autophagic process [148 149] As a proof of conceptin vivo delivery in mice of a specific autophagy inducerpeptide Tat-Beclin1 has demonstrated positive results in thetreatment of neurodegenerative disease and viral infections[150] However considering the multiple roles of autophagyfurther investigations are needed to examine in which situa-tions stimulated autophagy is beneficial anddoes not generatedetrimental side effects

Conflict of Interests

The authors declare that they have no conflict of interests

Acknowledgments

This work was supported by the Ministere de lrsquoEducationNational de lrsquoEnseignement Superieur et de la RechercheUniversite de Bourgogne Conseil Regional de Bourgogneand Institut National de la Recherche Agronomique (INRA)

References

[1] Y Feng D He Z Yao and D J Klionsky ldquoThe machinery ofmacroautophagyrdquo Cell Research vol 24 no 1 pp 24ndash41 2014

[2] G Kroemer G Marino and B Levine ldquoAutophagy and theintegrated stress responserdquo Molecular Cell vol 40 no 2 pp280ndash293 2010

[3] D N Cook D S Pisetsky and D A Schwartz ldquoToll-like recep-tors in the pathogenesis of human diseaserdquoNature Immunologyvol 5 no 10 pp 975ndash979 2004

[4] W-W Li J Li and J-K Bao ldquoMicroautophagy lesser-knownself-eatingrdquo Cellular and Molecular Life Sciences vol 69 no 7pp 1125ndash1136 2012

[5] S Kaushik and A M Cuervo ldquoChaperone-mediated auto-phagy a unique way to enter the lysosomeworldrdquoTrends in CellBiology vol 22 no 8 pp 407ndash417 2012

[6] A Stolz A Ernst and I Dikic ldquoCargo recognition andtrafficking in selective autophagyrdquo Nature Cell Biology vol 16no 6 pp 495ndash501 2014

[7] C T Chu H Bayir and V E Kagan ldquoLC3 binds externalizedcardiolipin on injured mitochondria to signal mitophagy inneurons Implications for Parkinson diseaserdquo Autophagy vol10 no 2 pp 376ndash378 2014

[8] G Ashrafi and T L Schwarz ldquoThe pathways of mitophagy forquality control and clearance of mitochondriardquo Cell Death andDifferentiation vol 20 no 1 pp 31ndash42 2013

[9] C He and B Levine ldquoThe Beclin 1 interactomerdquo CurrentOpinion in Cell Biology vol 22 no 2 pp 140ndash149 2010

[10] D G McEwan and I Dikic ldquoThe three musketeers ofautophagy phosphorylation ubiquitylation and acetylationrdquoTrends in Cell Biology vol 21 no 4 pp 195ndash201 2011

[11] J Kim M Kundu B Viollet and K-L Guan ldquoAMPK andmTOR regulate autophagy through direct phosphorylation ofUlk1rdquo Nature Cell Biology vol 13 no 2 pp 132ndash141 2011

[12] C A Mercer A Kaliappan and P B Dennis ldquoA novel humanAtg13 binding protein Atg101 interacts with ULK1 and isessential formacroautophagyrdquoAutophagy vol 5 no 5 pp 649ndash662 2009

[13] B O Bodemann A Orvedahl T Cheng et al ldquoRalB andthe exocyst mediate the cellular starvation response by directactivation of autophagosome assemblyrdquo Cell vol 144 no 2 pp253ndash267 2011

[14] T Proikas-Cezanne Z Takacs P Donnes and O KohlbacherldquoWIPI proteins essential PtdIns3P effectors at the nascentautophagosomerdquo Journal of Cell Science vol 128 no 2 pp 207ndash217 2015

[15] Y Kabeya N Mizushima T Ueno et al ldquoLC3 a mammalianhomologue of yeast Apg8p is localized in autophagosomemembranes after processingrdquoThe EMBO Journal vol 19 no 21pp 5720ndash5728 2000

[16] K Moreau B Ravikumar M Renna C Puri and D CRubinsztein ldquoAutophagosome precursor maturation requireshomotypic fusionrdquo Cell vol 146 no 2 pp 303ndash317 2011

[17] H Yamamoto S Kakuta T M Watanabe et al ldquoAtg9 vesiclesare an important membrane source during early steps ofautophagosome formationrdquo Journal of Cell Biology vol 198 no2 pp 219ndash233 2012

[18] N Fujita M Hayashi-Nishino H Fukumoto et al ldquoAn Atg4Bmutant hampers the lipidation of LC3 paralogues and causesdefects in autophagosome closurerdquoMolecular Biology of the Cellvol 19 no 11 pp 4651ndash4659 2008

[19] L Jahreiss F MMenzies and D C Rubinsztein ldquoThe itineraryof autophagosomes from peripheral formation to kiss-and-runfusion with lysosomesrdquo Traffic vol 9 no 4 pp 574ndash587 2008

[20] CM Fader D SanchezM Furlan andM I Colombo ldquoInduc-tion of autophagy promotes fusion of multivesicular bodieswith autophagic vacuoles in K562 cellsrdquo Traffic vol 9 no 2pp 230ndash250 2008

[21] C M Fader D G Sanchez M B Mestre and M I ColomboldquoTI-VAMPVAMP7 and VAMP3cellubrevin two v-SNAREproteins involved in specific steps of the autophagymultivesic-ular body pathwaysrdquo Biochimica et Biophysica ActamdashMolecularCell Research vol 1793 no 12 pp 1901ndash1916 2009

[22] C Liang J-S Lee K-S Inn et al ldquoBeclin1-binding UVRAGtargets the class C Vps complex to coordinate autophagosomematuration and endocytic traffickingrdquo Nature Cell Biology vol10 no 7 pp 776ndash787 2008

[23] Z Yang J Huang J Geng U Nair and D J Klionsky ldquoAtg22recycles amino acids to link the degradative and recyclingfunctions of autophagyrdquo Molecular Biology of the Cell vol 17no 12 pp 5094ndash5104 2006

[24] L Yu C K McPhee L Zheng et al ldquoTermination of autophagyand reformation of lysosomes regulated by mTORrdquoNature vol465 no 7300 pp 942ndash946 2010


[25] I M Dambuza and G D Brown ldquoC-type lectins in immunityrecent developmentsrdquo Current Opinion in Immunology vol 32pp 21ndash27 2014

[26] M Yoneyama K Onomoto M Jogi T Akaboshi and T FujitaldquoViral RNA detection by RIG-I-like receptorsrdquoCurrent Opinionin Immunology vol 32 pp 48ndash53 2015

[27] T Kawasaki and T Kawai ldquoToll-like receptor signaling path-waysrdquo Frontiers in Immunology vol 5 article 461 2014

[28] V Motta F Soares T Sun and D J Philpott ldquoNOD-like recep-tors versatile cytosolic sentinelsrdquo Physiological Reviews vol 95no 1 pp 149ndash178 2015

[29] A T Gewirtz T A Navas S Lyons P J Godowski and J LMadara ldquoCutting edge bacterial flagellin activates basolaterallyexpressed TLR5 to induce epithelial proinflammatory geneexpressionrdquo Journal of Immunology vol 167 no 4 pp 1882ndash1885 2001

[30] M A Delgado R A Elmaoued A S Davis G Kyei and VDeretic ldquoToll-like receptors control autophagyrdquo EMBO Journalvol 27 no 7 pp 1110ndash1121 2008

[31] C-S Shi and J H Kehrl ldquoMyD88 and Trif target Beclin 1 totrigger autophagy in macrophagesrdquo The Journal of BiologicalChemistry vol 283 no 48 pp 33175ndash33182 2008

[32] S Bertin and V Pierrefite-Carle ldquoAutophagy and toll-likereceptors a new link in cancer cellsrdquo Autophagy vol 4 no 8pp 1086ndash1089 2008

[33] P K Anand S W G Tait M Lamkanfi et al ldquoTLR2 and RIP2pathways mediate autophagy of Listeria monocytogenes viaextracellular signal-regulated kinase (ERK) activationrdquo TheJournal of Biological Chemistry vol 286 no 50 pp 42981ndash42991 2011

[34] L Fang H-M Wu P-S Ding and R-Y Liu ldquoTLR2 mediatesphagocytosis and autophagy through JNK signaling pathwayin Staphylococcus aureus-stimulated RAW2647 cellsrdquo CellularSignalling vol 26 no 4 pp 806ndash814 2014

[35] Y Xu C Jagannath X-D Liu A Sharafkhaneh K EKolodziejska and N T Eissa ldquoToll-like receptor 4 is a sensorfor autophagy associated with innate immunityrdquo Immunity vol27 no 1 pp 135ndash144 2007

[36] F Schmitz A Heit S Dreher et al ldquoMammalian target ofrapamycin (mTOR) orchestrates the defense program of innateimmune cellsrdquo European Journal of Immunology vol 38 no 11pp 2981ndash2992 2008

[37] M van der Vaart C J Korbee G E Lamers et al ldquoTheDNA damage-regulated autophagy modulator DRAM1 linksmycobacterial recognition via TLR-MYD88 to autophagicdefenserdquo Cell Host amp Microbe vol 15 no 6 pp 753ndash767 2014

[38] R Cooney J Baker O Brain et al ldquoNOD2 stimulation inducesautophagy in dendritic cells influencing bacterial handling andantigen presentationrdquo Nature Medicine vol 16 no 1 pp 90ndash972010

[39] L H Travassos L A M Carneiro M Ramjeet et al ldquoNod1 andNod2 direct autophagy by recruiting ATG16L1 to the plasmamembrane at the site of bacterial entryrdquo Nature Immunologyvol 11 no 1 pp 55ndash62 2010

[40] T Yano S Mita H Ohmori et al ldquoAutophagic control oflisteria through intracellular innate immune recognition indrosophilardquo Nature Immunology vol 9 no 8 pp 908ndash9162008

[41] B G Byrne J F Dubuisson A D Joshi J J Persson and MS Swanson ldquoInflammasome components coordinate autophagyand pyroptosis as macrophage responses to infectionrdquo MBiovol 4 no 1 2013

[42] J D Martins J Liberal A Silva I Ferreira B M Neves andMT Cruz ldquoAutophagy and inflammasome interplayrdquoDNAandCell Biology vol 34 no 4 pp 274ndash281 2015

[43] C-S Shi K Shenderov N-N Huang et al ldquoActivation ofautophagy by inflammatory signals limits IL-1120573 production bytargeting ubiquitinated inflammasomes for destructionrdquoNatureImmunology vol 13 no 3 pp 255ndash263 2012

[44] N Jounai K Kobiyama M Shiina K Ogata K J Ishii andF Takeshita ldquoNLRP4 negatively regulates autophagic processesthrough an association with Beclin1rdquo Journal of Immunologyvol 186 no 3 pp 1646ndash1655 2011

[45] J Harris ldquoAutophagy and cytokinesrdquoCytokine vol 56 no 2 pp140ndash144 2011

[46] MAAl-ZeerHMAl-Younes P R Braun J Zerrahn andT FMeyer ldquoIFN-120574-inducible Irga6 mediates host resistance againstChlamydia trachomatis via autophagyrdquo PLoS ONE vol 4 no 2Article ID e4588 2009

[47] M G Gutierrez S S Master S B Singh G A Taylor M IColombo and V Deretic ldquoAutophagy is a defense mechanisminhibiting BCG and Mycobacterium tuberculosis survival ininfected macrophagesrdquo Cell vol 119 no 6 pp 753ndash766 2004

[48] B-H Kim A R Shenoy P Kumar R Das S Tiwari and JD MacMicking ldquoA family of IFN-120574-inducible 65-kD GTPasesprotects against bacterial infectionrdquo Science vol 332 no 6030pp 717ndash721 2011

[49] S B Singh A S Davis G A Taylor and V Deretic ldquoHumanIRGM induces autophagy to eliminate intracellular mycobacte-riardquo Science vol 313 no 5792 pp 1438ndash1441 2006

[50] C Bekpen J P Hunn C Rohde et al ldquoThe interferon-induciblep47 (IRG) GTPases in vertebrates loss of the cell autonomousresistance mechanism in the human lineagerdquo Genome Biologyvol 6 no 11 article R92 2005

[51] P Brest P Lapaquette M Souidi et al ldquoA synonymous variantin IRGM alters a binding site for miR-196 and causes deregula-tion of IRGM-dependent xenophagy in Crohnrsquos diseaserdquoNatureGenetics vol 43 no 3 pp 242ndash245 2011

[52] C D Intemann T Thye S Niemann et al ldquoAutophagy genevariant IRGM-261T contributes to protection from tuberculosiscaused byMycobacterium tuberculosis but not by119872 119886119891119903119894119888119886119899119906119898strainsrdquo PLoS Pathogens vol 5 no 9 Article ID e1000577 2009

[53] TMatsuzawa B-H KimA R Shenoy S KamitaniMMiyakeand J D MacMicking ldquoIFN-gamma elicits macrophageautophagy via the p38 MAPK signaling pathwayrdquo Journal ofImmunology vol 189 no 2 pp 813ndash818 2012

[54] P LiQDu ZCao et al ldquoInterferon-gamma induces autophagywith growth inhibition and cell death in human hepatocellularcarcinoma (HCC) cells through interferon-regulatory factor-1(IRF-1)rdquo Cancer Letters vol 314 no 2 pp 213ndash222 2012

[55] H Schmeisser J Bekisz and K C Zoon ldquoNew function ofType I IFN induction of autophagyrdquo Journal of Interferon andCytokine Research vol 34 no 2 pp 71ndash78 2014

[56] M Djavaheri-Mergny M Amelotti J Mathieu et al ldquoNF-120581B activation represses tumor necrosis factor-120572-inducedautophagyrdquoThe Journal of Biological Chemistry vol 281 no 41pp 30373ndash30382 2006

[57] L Jia R R Dourmashkin P D Allen A B Gray A CNewland and S M Kelsey ldquoInhibition of autophagy abrogatestumour necrosis factor alpha induced apoptosis in human T-lymphoblastic leukaemic cellsrdquo British Journal of Haematologyvol 98 no 3 pp 673ndash685 1997


[58] N-Y Lin C Beyer A Gieszligl et al ldquoAutophagy regulates TNF120572-mediated joint destruction in experimental arthritisrdquo Annals ofthe Rheumatic Diseases vol 72 no 5 pp 761ndash768 2013

[59] N Baregamian J Song C E Bailey J Papaconstantinou BM Evers and D H Chung ldquoTumor necrosis factor-alpha andapoptosis signal-regulating kinase 1 control reactive oxygenspecies release mitochondrial autophagy and c-Jun N-terminalkinasep38 phosphorylation during necrotizing enterocolitisrdquoOxidativeMedicine and Cellular Longevity vol 2 no 5 pp 297ndash306 2009

[60] M Djavaheri-Mergny M Amelotti J Mathieu F BesanconC Bauvy and P Codogno ldquoRegulation of autophagy by NF120581Btranscription factor and reactives oxygen speciesrdquo Autophagyvol 3 no 4 pp 390ndash392 2007

[61] G Jia G Cheng D M Gangahar and D K Agrawal ldquoInsulin-like growth factor-1 and TNF-120572 regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atheroscle-rotic vascular smooth cellsrdquo Immunology and Cell Biology vol84 no 5 pp 448ndash454 2006

[62] U Sivaprasad and A Basu ldquoInhibition of ERK attenuatesautophagy and potentiates tumour necrosis factor-alpha-induced cell death in MCF-7 cellsrdquo Journal of Cellular andMolecular Medicine vol 12 no 4 pp 1265ndash1271 2008

[63] J Harris J C Hope and J Keane ldquoTumor necrosis factorblockers influence macrophage responses to Mycobacteriumtuberculosisrdquo Journal of Infectious Diseases vol 198 no 12 pp1842ndash1850 2008

[64] J Harris and J Keane ldquoHow tumour necrosis factor blockersinterfere with tuberculosis immunityrdquo Clinical and Experimen-tal Immunology vol 161 no 1 pp 1ndash9 2010

[65] H Roca Z S Varcos S SudM J Craig andK J Pienta ldquoCCL2and interleukin-6 promote survival of human CD11b+ periph-eral blood mononuclear cells and induce M2-type macrophagepolarizationrdquo The Journal of Biological Chemistry vol 284 no49 pp 34342ndash34354 2009

[66] Q Zhang R Kang H J ZehM T Lotze andD Tang ldquoDAMPsand autophagy cellular adaptation to injury and unscheduledcell deathrdquo Autophagy vol 9 no 4 pp 451ndash458 2013

[67] Y Qi M Zhang H Li et al ldquoAutophagy inhibition by sustainedoverproduction of IL6 contributes to arsenic carcinogenesisrdquoCancer Research vol 74 no 14 pp 3740ndash3752 2014

[68] E D Smith G A Prieto L Tong et al ldquoRapamycin andinterleukin-1120573 impair brain-derived neurotrophic factor-dependent neuron survival by modulating autophagyrdquo TheJournal of Biological Chemistry vol 289 no 30 pp 20615ndash20629 2014

[69] Y Ding and M E Choi ldquoRegulation of autophagy by TGF-120573emerging role in kidney fibrosisrdquo Seminars in Nephrology vol34 no 1 pp 62ndash71 2014

[70] Y Ding J K Kim S I Kim et al ldquoTGF-1205731 protects againstmesangial cell apoptosis via induction of autophagyrdquo Journal ofBiological Chemistry vol 285 no 48 pp 37909ndash37919 2010

[71] J Harris S A de Haro S S Master et al ldquoT helper 2 cytokinesinhibit autophagic control of intracellularMycobacterium tuber-culosisrdquo Immunity vol 27 no 3 pp 505ndash517 2007

[72] H-J Park S J Lee S-H Kim et al ldquoIL-10 inhibits thestarvation induced autophagy in macrophages via class I phos-phatidylinositol 3-kinase (PI3K) pathwayrdquoMolecular Immunol-ogy vol 48 no 4 pp 720ndash727 2011

[73] A-L Levonen B G Hill E Kansanen J Zhang and V MDarley-Usmar ldquoRedox regulation of antioxidants autophagy

and the response to stress implications for electrophile thera-peuticsrdquo Free Radical Biology andMedicine vol 71 pp 196ndash2072014

[74] E Desideri G Filomeni and M R Ciriolo ldquoGlutathioneparticipates in themodulation of starvation-induced autophagyin carcinoma cellsrdquoAutophagy vol 8 no 12 pp 1769ndash1781 2012

[75] D M Gwinn D B Shackelford D F Egan et al ldquoAMPKphosphorylation of raptor mediates a metabolic checkpointrdquoMolecular Cell vol 30 no 2 pp 214ndash226 2008

[76] K Inoki H Ouyang T Zhu et al ldquoTSC2 integrates Wnt andenergy signals via a coordinated phosphorylation byAMPKandGSK3 to regulate cell growthrdquo Cell vol 126 no 5 pp 955ndash9682006

[77] R Scherz-Shouval E Shvets and Z Elazar ldquoOxidation asa post-translational modification that regulates autophagyrdquoAutophagy vol 3 no 4 pp 371ndash373 2007

[78] Z-Q Yu T Ni B Hong et al ldquoDual roles of Atg8-PE decon-jugation byAtg4 in autophagyrdquoAutophagy vol 8 no 6 pp 883ndash892 2012

[79] T Copetti C Bertoli E Dalla F Demarchi and C Schneiderldquop65RelA modulates BECN1 transcription and autophagyrdquoMolecular and Cellular Biology vol 29 no 10 pp 2594ndash26082009

[80] J Ling Y Kang R Zhao et al ldquoKrasG12D-induced IKK2120573NF-120581B activation by IL-1120572 and p62 feedforward loops is requiredfor development of pancreatic ductal adenocarcinomardquo CancerCell vol 21 no 1 pp 105ndash120 2012

[81] J Fullgrabe D J Klionsky and B Joseph ldquoThe return of thenucleus transcriptional and epigenetic control of autophagyrdquoNature Reviews Molecular Cell Biology vol 15 no 1 pp 65ndash742014

[82] G Bellot R Garcia-Medina P Gounon et al ldquoHypoxia-induced autophagy is mediated through hypoxia-induciblefactor induction of BNIP3 and BNIP3L via their BH3 domainsrdquoMolecular and Cellular Biology vol 29 no 10 pp 2570ndash25812009

[83] D-D Li L-L Wang R Deng et al ldquoThe pivotal role of c-JunNH2-terminal kinase-mediatedBeclin 1 expression during anti-cancer agents-induced autophagy in cancer cellsrdquo Oncogenevol 28 no 6 pp 886ndash898 2009

[84] T Sun D Li L Wang et al ldquoC-Jun NH2-terminal kinase acti-vation is essential for up-regulation of LC3 during ceramide-induced autophagy in human nasopharyngeal carcinoma cellsrdquoJournal of Translational Medicine vol 9 no 1 article 161 2011

[85] D J Dauer B Ferraro L Song et al ldquoStat3 regulates genescommon to both wound healing and cancerrdquoOncogene vol 24no 21 pp 3397ndash3408 2005

[86] J Mccormick N Suleman T M Scarabelli R A KnightD S Latchman and A Stephanou ldquoSTAT1 deficiency in theheart protects against myocardial infarction by enhancingautophagyrdquo Journal of Cellular and Molecular Medicine vol 16no 2 pp 386ndash393 2012

[87] J M Lee M Wagner R Xiao et al ldquoNutrient-sensing nuclearreceptors coordinate autophagyrdquo Nature vol 516 no 7529 pp112ndash115 2014

[88] J Zhou W Zhang B Liang et al ldquoPPAR120574 activation inducesautophagy in breast cancer cellsrdquo International Journal ofBiochemistry and Cell Biology vol 41 no 11 pp 2334ndash23422009

[89] C Settembre C di Malta V A Polito et al ldquoTFEB linksautophagy to lysosomal biogenesisrdquo Science vol 332 no 6036pp 1429ndash1433 2011


[90] T Nunes and H S de Souza ldquoInflammasome in intestinalinflammation and cancerrdquoMediators of Inflammation vol 2013Article ID 654963 8 pages 2013

[91] T Saitoh N Fujita M H Jang et al ldquoLoss of the autophagyprotein Atg16L1 enhances endotoxin-induced IL-1beta produc-tionrdquo Nature vol 456 no 7219 pp 264ndash268 2008

[92] K Nakahira J A Haspel V A K Rathinam et al ldquoAutophagyproteins regulate innate immune responses by inhibiting therelease of mitochondrial DNA mediated by the NALP3 inflam-masomerdquo Nature Immunology vol 12 no 3 pp 222ndash230 2011

[93] J Harris M Hartman C Roche et al ldquoAutophagy controls IL-1120573 secretion by targetingPro-IL-1120573 for degradationrdquoTheJournalof Biological Chemistry vol 286 no 11 pp 9587ndash9597 2011

[94] R Zhou A S Yazdi P Menu and J Tschopp ldquoA role formitochondria inNLRP3 inflammasome activationrdquoNature vol475 no 7354 pp 122ndash225 2011

[95] G Matsumoto K Wada M Okuno M Kurosawa and NNukina ldquoSerine 403 phosphorylation of p62SQSTM1 regulatesselective autophagic clearance of ubiquitinated proteinsrdquoMolec-ular Cell vol 44 no 2 pp 279ndash289 2011

[96] M T Sorbara and S E Girardin ldquoEmerging themes in bacterialautophagyrdquo Current Opinion inMicrobiology C vol 23 pp 163ndash170 2015

[97] A Duran R Amanchy J F Linares et al ldquoP62 is a key regulatorof nutrient sensing in the mTORC1 pathwayrdquo Molecular Cellvol 44 no 1 pp 134ndash146 2011

[98] M Komatsu H Kurokawa S Waguri et al ldquoThe selectiveautophagy substrate p62 activates the stress responsive tran-scription factor Nrf2 through inactivation of Keap1rdquoNature CellBiology vol 12 no 3 pp 213ndash223 2010

[99] V Deretic S Jiang and N Dupont ldquoAutophagy intersectionswith conventional and unconventional secretion in tissue devel-opment remodeling and inflammationrdquo Trends in Cell Biologyvol 22 no 8 pp 397ndash406 2012

[100] C Rabouille V Malhotra and W Nickel ldquoDiversity in uncon-ventional protein secretionrdquo Journal of Cell Science vol 125 no22 pp 5251ndash5255 2012

[101] N Dupont S Jiang M Pilli W Ornatowski D Bhattacharyaand V Deretic ldquoAutophagy-based unconventional secretorypathway for extracellular delivery of IL-1betardquo The EMBOJournal vol 30 no 23 pp 4701ndash4711 2011

[102] L B Ivashkiv ldquoEpigenetic regulation of macrophage polariza-tion and functionrdquo Trends in Immunology vol 34 no 5 pp216ndash223 2013

[103] T Lawrence and G Natoli ldquoTranscriptional regulation ofmacrophage polarization enabling diversity with identityrdquoNature Reviews Immunology vol 11 no 11 pp 750ndash761 2011

[104] A Sica and AMantovani ldquoMacrophage plasticity and polariza-tion in vivo veritasrdquo Journal of Clinical Investigation vol 122no 3 pp 787ndash795 2012

[105] E Cassol L Cassetta C Rizzi M Alfano and G Poli ldquoM1 andM2a polarization of human monocyte-derived macrophagesinhibits HIV-1 replication by distinct mechanismsrdquoThe Journalof Immunology vol 182 no 10 pp 6237ndash6246 2009

[106] C-P Chang Y-C Su C-W Hu and H-Y Lei ldquoTLR2-dependent selective autophagy regulates NF-120581B lysosomaldegradation in hepatoma-derived M2 macrophage differentia-tionrdquo Cell Death and Differentiation vol 20 no 3 pp 515ndash5232013

[107] C-P Chang Y-C Su P-H Lee andH-Y Lei ldquoTargetingNFKBby autophagy to polarize hepatoma-associated macrophagedifferentiationrdquo Autophagy vol 9 no 4 pp 619ndash621 2013

[108] W Chen T Ma X-N Shen et al ldquoMacrophage-induced tumorangiogenesis is regulated by the TSC2-mTOR pathwayrdquo CancerResearch vol 72 no 6 pp 1363ndash1372 2012

[109] M Yang J Liu J Shao et al ldquoCathepsin S-mediated autophagicflux in tumor-associated macrophages accelerate tumor devel-opment by promoting M2 polarizationrdquoMolecular Cancer vol13 no article 43 2014

[110] AM K Choi SW Ryter and B Levine ldquoAutophagy in humanhealth and diseaserdquo The New England Journal of Medicine vol368 no 7 pp 651ndash662 2013

[111] C Huttenhower A Kostic and R Xavier ldquoInflammatory boweldisease as a model for translating the microbiomerdquo Immunityvol 40 no 6 pp 843ndash854 2014

[112] J D Rioux R J Xavier K D Taylor et al ldquoGenome-wideassociation study identifies new susceptibility loci for Crohndisease and implicates autophagy in disease pathogenesisrdquoNature Genetics vol 39 no 5 pp 596ndash604 2007

[113] J C Barrett S Hansoul D L Nicolae et al ldquoGenome-wideassociation defines more than 30 distinct susceptibility loci forCrohnrsquos diseaserdquo Nature Genetics vol 40 no 8 pp 955ndash9622008

[114] M Parkes J C Barrett N J Prescott et al ldquoSequence variantsin the autophagy gene IRGM andmultiple other replicating locicontribute to Crohnrsquos disease susceptibilityrdquo Nature Geneticsvol 39 no 7 pp 830ndash832 2007

[115] D Ellinghaus H Zhang S Zeissig et al ldquoAssociation betweenvariants of PRDM1 and NDP52 and crohnrsquos disease based onexome sequencing and functional studiesrdquo Gastroenterologyvol 145 no 2 pp 339ndash347 2013

[116] L Jostins S Ripke R K Weersma et al ldquoHost-microbe inter-actions have shaped the genetic architecture of inflammatorybowel diseaserdquo Nature vol 491 no 7422 pp 119ndash124 2012

[117] R J Palomino-Morales J Oliver M Gomez-Garcıa et alldquoAssociation of ATG16L1 and IRGM genes polymorphisms withinflammatory bowel disease a meta-analysis approachrdquo Genesand Immunity vol 10 no 4 pp 356ndash364 2009

[118] S A McCarroll A Huett P Kuballa et al ldquoDeletion poly-morphism upstream of IRGM associated with altered IRGMexpression and Crohnrsquos diseaserdquo Nature Genetics vol 40 no 9pp 1107ndash1112 2008

[119] L Henckaerts I Cleynen M Brinar et al ldquoGenetic variationin the autophagy gene ULK1 and risk of Crohnrsquos diseaserdquoInflammatory Bowel Diseases vol 17 no 6 pp 1392ndash1397 2011

[120] M Brinar S Vermeire I Cleynen et al ldquoGenetic variants inautophagy-related genes and granuloma formation in a cohortof surgically treated Crohnrsquos disease patientsrdquo Journal of Crohnrsquosand Colitis vol 6 no 1 pp 43ndash50 2012

[121] J-P Hugot M Chamaillard H Zouali et al ldquoAssociationof NOD2 leucine-rich repeat variants with susceptibility toCrohnrsquos diseaserdquo Nature vol 411 no 6837 pp 599ndash603 2001

[122] Y Ogura D K Bonen N Inohara et al ldquoA frameshiftmutationin NOD2 associated with susceptibility to Crohnrsquos diseaserdquoNature vol 411 no 6837 pp 603ndash606 2001

[123] M T Sorbara L K Ellison M Ramjeet et al ldquoThe pro-tein ATG16L1 suppresses inflammatory cytokines induced bythe intracellular sensors Nod1 and Nod2 in an autophagy-independent mannerrdquo Immunity vol 39 no 5 pp 858ndash8732013

[124] A Kaser EMartınez-Naves and R S Blumberg ldquoEndoplasmicreticulum stress implications for inflammatory bowel diseasepathogenesisrdquo Current Opinion in Gastroenterology vol 26 no4 pp 318ndash326 2010


[125] A Kaser A-H Lee A Franke et al ldquoXBP1 links ER stressto intestinal inflammation and confers genetic risk for humaninflammatory bowel diseaserdquo Cell vol 134 no 5 pp 743ndash7562008

[126] F Zhao R Edwards D Dizon et al ldquoDisruption of Paneth andgoblet cell homeostasis and increased endoplasmic reticulumstress in Agr2-- micerdquo Developmental Biology vol 338 no 2pp 270ndash279 2010

[127] A Bertolotti X Wang I Novoa et al ldquoIncreased sensitivity todextran sodium sulfate colitis in IRE1beta-deficient micerdquo TheJournal of Clinical Investigation vol 107 no 5 pp 585ndash593 2001

[128] J J Deuring C de Haar C L Koelewijn E J KuipersM P Peppelenbosch and C J van der Woude ldquoAbsence ofABCG2-mediated mucosal detoxification in patients withactive inflammatory bowel disease is due to impeded proteinfoldingrdquo Biochemical Journal vol 441 no 1 pp 87ndash93 2012

[129] A Shkoda P A Ruiz H Daniel et al ldquoInterleukin-10 blockedendoplasmic reticulum stress in intestinal epithelial cellsimpact on chronic inflammationrdquoGastroenterology vol 132 no1 pp 190ndash207 2007

[130] T E Adolph M F Tomczak L Niederreiter et al ldquoPaneth cellsas a site of origin for intestinal inflammationrdquo Nature vol 503no 7475 pp 272ndash276 2013

[131] L Yang P Li S Fu E S Calay andG SHotamisligil ldquoDefectivehepatic autophagy in obesity promotes ER stress and causesinsulin resistancerdquo Cell Metabolism vol 11 no 6 pp 467ndash4782010

[132] J J Deuring G M Fuhler S R Konstantinov et al ldquoGenomicATG16L1 risk allele-restricted Paneth cell ER stress in quiescentCrohnrsquos diseaserdquo Gut vol 63 no 7 pp 1081ndash1091 2014

[133] I Tattoli M T Sorbara D Vuckovic et al ldquoAmino acidstarvation induced by invasive bacterial pathogens triggers aninnate host defense programrdquo Cell Host andMicrobe vol 11 no6 pp 563ndash575 2012

[134] C Manichanh N Borruel F Casellas and F Guarner ldquoThegut microbiota in IBDrdquo Nature Reviews Gastroenterology andHepatology vol 9 no 10 pp 599ndash608 2012

[135] B Chassaing and A Darfeuille-michaud ldquoThe commensalmicrobiota and enteropathogens in the pathogenesis of inflam-matory bowel diseasesrdquo Gastroenterology vol 140 no 6 pp1720ndash1728 2011

[136] M Martinez-Medina and L J Garcia-Gil ldquoEscherichia coli inchronic inflammatory bowel diseases an update on adherentinvasive Escherichia coli pathogenicityrdquo World Journal of Gas-trointestinal Pathophysiology vol 5 pp 213ndash227 2014

[137] M Sadaghian Sadabad A Regeling M C de Goffau et al ldquoTheATG16L1-T300A allele impairs clearance of pathosymbionts inthe inflamed ilealmucosa of Crohnrsquos disease patientsrdquoGut 2014

[138] J L Benjamin R Sumpter Jr B Levine and L V HooperldquoIntestinal epithelial autophagy is essential for host defenseagainst invasive bacteriardquo Cell Host and Microbe vol 13 no 6pp 723ndash734 2013

[139] P Lapaquette M-A Bringer and A Darfeuille-MichaudldquoDefects in autophagy favour adherent-invasive Escherichiacoli persistence within macrophages leading to increased pro-inflammatory responserdquoCellularMicrobiology vol 14 no 6 pp791ndash807 2012

[140] P Lapaquette A-L Glasser A Huett R J Xavier andA Darfeuille-Michaud ldquoCrohnrsquos disease-associated adherent-invasive E coli are selectively favoured by impaired autophagyto replicate intracellularlyrdquo Cellular Microbiology vol 12 no 1pp 99ndash113 2010

[141] J W Symington C Wang J Twentyman et al ldquoATG16L1deficiency inmacrophages drives clearance of uropathogenic Ecoli in an IL-1120573-dependent mannerrdquo Mucosal Immunology2015

[142] C Wang G R Mendonsa J W Symington et al ldquoAtg16L1deficiency confers protection from uropathogenic Escherichiacoli infection in vivordquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 27 pp11008ndash11013 2012

[143] H T T Nguyen G Dalmasso S Muller J Carriere F Seiboldand A Darfeuille-Michaud ldquoCrohnrsquos disease-associated adher-ent invasive Escherichia coli modulate levels of microRNAs inintestinal epithelial cells to reduce autophagyrdquoGastroenterologyvol 146 no 2 pp 508ndash519 2014

[144] F Madeo N Tavernarakis and G Kroemer ldquoCan autophagypromote longevityrdquo Nature Cell Biology vol 12 no 9 pp 842ndash846 2010

[145] A M Cuervo and J F Dice ldquoAge-related decline in chaperone-mediated autophagyrdquo The Journal of Biological Chemistry vol275 no 40 pp 31505ndash31513 2000

[146] M Michaud L Balardy G Moulis et al ldquoProinflammatorycytokines aging and age-related diseasesrdquo Journal of the Amer-ican Medical Directors Association vol 14 no 12 pp 877ndash8822013

[147] S Huang M-A Bjornsti and P J Houghton ldquoRapamycinsmechanism of action and cellular resistancerdquo Cancer BiologyandTherapy vol 2 no 3 pp 222ndash232 2003

[148] A D Balgi B D Fonseca E Donohue et al ldquoScreen forchemical modulators of autophagy reveals novel therapeuticinhibitors of mTORC1 signalingrdquo PLoS ONE vol 4 no 9Article ID e7124 2009

[149] L Zhang J Yu H Pan et al ldquoSmall molecule regulatorsof autophagy identified by an image-based high-throughputscreenrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 48 pp 19023ndash19028 2007

[150] S Shoji-Kawata R Sumpter M Leveno et al ldquoIdentification ofa candidate therapeutic autophagy-inducing peptiderdquo Naturevol 494 no 7436 pp 201ndash206 2013

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


mediators and autophagy it is nearly impossible to becompletely exhaustive but we will highlight some of the best-characterized interactions between these two processes Inthe last part of the review we will discuss in more detailthe crosstalk between autophagy and inflammation duringpathophysiological situations especially inflammatory boweldiseases

2 Autophagy How Does It Work

21 Different Types of Autophagy Three main forms ofautophagy have been described in mammalians Macroau-tophagy corresponds to the sequestration of cytoplasmicstructures into double- or multimembrane vesicles termedautophagosomes Complete autophagosomes then transitalong microtubules to deliver their content to degradativecompartments lysosomes forming autolysosomes [1] Theterm microautophagy refers to the direct engulfment ofthe cytosolic material by invagination of the lysosomalmembrane [4] The third form of autophagy is chaperone-mediated autophagy (CMA) during which proteins contain-ing a pentapeptide motif (KFERQ-like sequence) are recog-nized by the cytosolic chaperone hsc70 (heat shock cognateprotein of 70 kDa) and its cochaperones that deliver themto the surface of lysosomes The substrate-chaperone com-plex binds to the lysosomal protein LAMP-2A (lysosome-associated membrane protein type 2A) and the substrateis unfolded Multimerization of LAMP-2A is required forsubstrate translocation inside the lysosome [5] In this reviewwe will focus only on macroautophagy (hereafter referredto as autophagy) and its interrelations with inflammatoryprocesses

Autophagy was first described as a nonselective bulkdegradation process sequestering a portion of the cytosoland used by the cell during nutrient deprivation periodIn light of studies during last decade it turns out thatautophagy can also be selective allowing under certainconditions the sequestration of specific substrates such asmitochondria (mitophagy) endoplasmic reticulum (ER- orreticulophagy) lipid droplets (lipophagy) peroxisomes (pex-ophagy) endosomes lysosomes secretory granules ribo-somes (ribophagy) cytoplasmic aggregates (aggregaphagy)inflammatory proteins and invading pathogens (xenophagy)[6] Structures targeted for destruction by autophagy areoften ubiquitinated A series of autophagy receptors termedSLRs for Sequestosome 1- (SQSTM1-) like receptors containubiquitin-binding domain (UBD) associated with a LIR(LC3-interacting region) motif and act as adaptors betweenK48- or K63-linked polyubiquitin chains on a targeted-substrate and ATG8 paralogs (LC3 GABARAP) bridgingautophagic cargoes to nascent autophagosomes [6]Membersof SLRs family include p62SQSTM1 NBR1 NDP52 andoptineurin Substrates can also be delivered to autophago-some in ubiquitin-independent manner as exemplified bymitophagy In some cases autophagy-mediated degradationofmitochondria relies on polyubiquitylation of proteins at theouter mitochondrial membrane and is dependent on PINK1(PTEN-induced putative kinase protein 1) and the E3 ligaseParkin In other cases however mitophagy is dependent on

mitochondrial outer-membrane proteins (eg NIX) that candirectly link mitochondria to autophagosomal membranesvia their own LIR domain Finally an alternative way hasbeen observed in neuronal cells and involves externalizationof an inner mitochondrial membrane phospholipid namedcardiolipin to the outer mitochondrial membrane and itsdirect recognition by LC3 [7 8]

22 Molecular Machinery of Autophagy Autophagy can bedivided into 6 main steps initiation vesicle nucleationelongation membrane elongation closure maturation anddegradation Initiation step leads to the formation of an isola-tionmembrane called phagophore most often in close vicin-ity with the endoplasmic reticulum (ER) Various organellesincluding the ER the Golgi apparatus mitochondria theplasma membrane and endosomes have been proposed toserve as membrane reservoir for phagophore generation andgrowth Initiation of autophagy requires two protein kinasescomplexes (i) the ULK12-ATG13-FIP200 complex whichis coupled with the autophagy suppressor TOR complex 1(mTORC1) and (ii) the Beclin1-Vps34-Vps15-ATG14 com-plex This last complex is usually inhibited by interactionswith proteins from the Golgi apparatus antiapoptotic Bcl2proteins and other signals transducers [9] Given the factthat autophagy is a highly dynamic process its activation islargely dependent on a set of posttranslational modificationssuch as phosphorylation acetylation and ubiquitylation [10]The mTORC1 complex consists of the mTOR kinase whichis a master cell-growth regulator integrating numerous intra-cellular and extracellular signals (growth factor nutrientsand cellular energy status) G120573L PRAS40 and raptor Underbasal condition the mTORC1 complex associates with theULK12-ATG13-FIP200 complex and phosphorylatesULK12and ATG13 resulting in the inhibition of ULK12 kinaseactivity Under stressful conditions (eg nutrient depriva-tion) AMPK activates ULK12 (in complex with ATG13and FIP200) directly by site-specific phosphorylation andindirectly by inhibiting mTORC1 [11] Dephosphorylationof mTOR-dependent inhibitory sites on the ULK12-ATG13-FIP200 complex releases ULK12 activity allowing autophos-phorylation of this complex and its interaction to theATG101 protein in an ATG13-dependent manner [12] Theseevents lead to the subsequent recruitment and activation ofthe Beclin1-ATG14-Vps34-Vps15 complex at the membraneinducing nascent phagophore formation This vesicle nucle-ation step relies on dynamic assembly of both autophagyinitiation complexes (ULK12-ATG13-ATG101-FIP200 andBeclin1-ATG14-Vps34-Vps15) on the exocyst a scaffoldingprotein complex involving the Ras-like small G-protein RalBand its effector Exo84 which acts as an activation platformfor core autophagy machinery [13] The Beclin1-associatedphosphatidylinositol 3-kinase class III Vps34 marks the sitewhere the phagophore emerges from the ER by generating aPI3P-enriched structure called omegasome This event leadsto the recruitment of PI3P-binding proteins such as DFCP1(double FYVE-containing protein 1) Alfy and WIPI (WD-repeat domain phosphoinositide interacting) family proteinsMembers of the WIPI family WIPI1 WIPI2 and WIPI4recognize PI3P accumulation at the nascent autophagosome

















































Autophagy



Damaged organelles

Elimination of

Infla

mm

atio

nIn

flam

mat

ion

TLRs

NLRs



IL-2

IL-1

IL-6

ROS

Atg genes

HIF1

STAT1STAT3

Jun

FXR




TNF-120572 IFN-120574

TGF-120573

NF-120581BNF-120581B





6 Conclusion






Acknowledgments


References

































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































































Autophagy



Damaged organelles

Elimination of

Infla

mm

atio

nIn

flam

mat

ion

TLRs

NLRs



IL-2

IL-1

IL-6

ROS

Atg genes

HIF1

STAT1STAT3

Jun

FXR




TNF-120572 IFN-120574

TGF-120573

NF-120581BNF-120581B





6 Conclusion






Acknowledgments


References

































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Acknowledgments


References

































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article cellular and molecular connections between

Documents