annurev-physiol-021014-071937

PH77CH19-Mizgerd ARI 10 January 2015 11:52

Dynamics of Lung Defense inPneumonia: Resistance,Resilience, and RemodelingLee J. Quinton1,2,3 and Joseph P. Mizgerd1,2,4,51Pulmonary Center and Departments of 2Medicine, 3Pathology and Laboratory Medicine,4Microbiology, and 5Biochemistry, Boston University School of Medicine, Boston,Massachusetts 02118; email: [email protected], [email protected]

Annu. Rev. Physiol. 2015. 77:40730

First published online as a Review in Advance onAugust 13, 2014

The Annual Review of Physiology is online atphysiol.annualreviews.org

This articles doi:10.1146/annurev-physiol-021014-071937

Copyright c 2015 by Annual Reviews.All rights reserved

Keywords

respiratory infection, innate immunity, cytokines, lung, STAT3, NF-B

Abstract

Pneumonia is initiated by microbes in the lung, but physiological processesintegrating responses across diverse cell types and organ systems dictate theoutcome of respiratory infection. Resistance, or actions of the host to eradi-cate living microbes, in the lungs involves a combination of innate and adap-tive immune responses triggered by air-space infection. Resilience, or theability of the host tissues to withstand the physiologically damaging effects ofmicrobial and immune activities, is equally complex, precisely regulated, anddeterminative. Both immune resistance and tissue resilience are dynamic andchange throughout the lifetime, but we are only beginning to understandsuch remodeling and how it contributes to the incidence of severe pneu-monias, which diminishes as childhood progresses and then increases againamong the elderly. Here, we review the concepts of resistance, resilience,and remodeling as they apply to pneumonia, highlighting recent advancesand current signicant knowledge gaps.

407

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


INTRODUCTION

Pneumonia is the second-greatest burden of disease worldwide, behind only ischemic heart disease(1). It is the leading cause of death from infection in the United States (2). More children die ofpneumonia than of other causes across the globe (3), and it is the most common reason forAmerican children to become hospitalized (4). For older Americans, approximately half of allinfectious disease hospitalizations and deaths are from pneumonia (5), which confers a greaterrisk of death than any of the other 10 most common reasons that the US elderly get hospitalized(6). As concerning as these statistics are, they underestimate pneumonias impact. Infections ofthe respiratory tract complicate many diseases [e.g., HIV/AIDS, chronic obstructive pulmonarydisease (COPD), cystic brosis, and more], which are unaccounted for in these assessments (4, 7).Furthermore, less immediate sequelae of pneumonia, such as cardiovascular disease andmyocardialinfarction (8), long-term defects in pulmonary function (9), and impaired cognitive abilities (10),are not factored into these disease burdens.

This review highlights biological responses elicited by lung infection and how they conferimmune resistance and tissue resilience. By immune resistance, we mean host pathways that,driven by innate and adaptive immunity, diminish the number of living pathogens during in-fection. Immune resistance effector functions directly kill or remove microbes, such as the gen-eration of hypochlorite by neutrophils. Affector mechanisms of immune resistance contributeindirectly, by the coordination of diverse activities to enhance effector efcacy and the conse-quent reduction of microbial numbers, like neutrophil recruitment elicited by chemokines. Bytissue resilience, we mean the ability of the host to withstand, endure, or tolerate the stressof a given microbial challenge (11, 12). Tissue resilience pathways do not alter microbial bur-dens, but they diminish the pathophysiology caused (directly and indirectly) by those microbes.Tissue resilience is essential for combating damage elicited by pathogens or by immune resis-tance pathways. Tissue resilience includes effector plus affector mechanisms, such as antiproteasesthat prevent digestion of the extracellular matrix plus the cytokines that stimulate antiproteaseexpression, respectively. We prefer the term resilience to the term tolerance when discussingmammalian infections, because immune functions are such a critical component of infection andbecause the common term tolerance has a very specic different meaning in relation to immunefunctions.

We focus on bacterial pneumonias because they are especially common and severe (13, 14).Viral and fungal pneumonias are also important, and we sometimes extrapolate from those toresistance and resilience processes that may apply to bacterial pneumonia, identifying etiologicagents involved when doing so.We include animal studies as well as observations and experimentsin humans. Animalmodels have strengths and limitations for elucidating the biology of pneumonia(15, 16). Our focus on the changes elicited by bacteria in the respiratory tract, and on how thosechanges then inuence immune resistance and tissue resilience, precludes extensive discussionof pathways functioning at baseline to help prevent lung infection and injury. Transcriptionalregulation is involved in changes mediating resistance and resilience. Two different transcriptionfactors, NF-B and STAT3, are especially implicated, and we propose that these factors facilitatedistinct resistance or resilience processes (Figure 1). In most but not all cases, NF-B drivesimmune resistance programs that are essential to microbial elimination but that can lead to lunginjury and other pathophysiological manifestations. Conversely, we consider STAT3 primarily asamediator of tissue resilience programs, although roles in resistance are also observed. STAT3 andother resilience pathways are essential for preventing injury, but excess can favor acute infectionand promote chronic lung diseases. These central paradigms are expanded below. Unfortunately,editorial constraints mean that many outstanding and relevant studies cannot be included. Rather

408 Quinton Mizgerd

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


Immuneresistance

Tissueresilience

NF-B

STAT3

Lung defense in pneumonia

ARDSShock

Multiorgan failureEmphysema

InfectionHyperplasiaMucus metaplasiaFibrosisCancer

Figure 1Lung defense requires a careful balance between immune resistance and tissue resilience pathways, shapedlargely by NF-B and STAT3, respectively. In response to lung infection, multiple signals are initiated tolimit the number of living pathogens in the respiratory tract, some of which are more broadly applicable thanothers (small versus large circles). NF-B represents a prominent signaling node for achieving such immuneresistance, driving the expression of numerous factors eliciting innate immunity and antimicrobial defense.Correspondingly, pathways must be initiated that enable pneumonic lung tissue to tolerate the netpathological consequences of both the infection and the resulting immune response. Gene programscontrolled by the STAT3 transcription factor promote such resilience by preserving tissue integrity andpreventing excessive inammation. Although the known functions of NF-B and STAT3 are skewed towardresistance and resilience, respectively, these pathways are capable of functioning in an opposite mannerthrough distinct and overlapping mechanisms, represented by intersections. Regardless of their dependenceon NF-B or STAT3, overexuberant resistance or resilience pathways are sufcient to drive lung diseasessuch as those indicated, demanding a controlled and balanced response. ARDS denotes acute respiratorydistress syndrome.

than summarizing the eld, we emphasize a few areas that we consider to be particularly topicaland timely.

RESISTANCE: CELL-SPECIFIC ROLES THAT INITIATE, DIRECT,AND AMPLIFY ANTIBACTERIAL INNATE IMMUNITY

NF-B and Innate Immunity Across Diverse Cell Types During Pneumonia

Without exception, initial interactions of microbes with the respiratory tract involve innate im-munity, the speed, amplitude, and direction of which are critical to resistance (17). A pivotalmediator of innate immune responses is canonical signaling of NF-B, whose transcriptionalactivity requires the RelA protein, also known as p65 (18). Targeted mutation of RelA in micecauses remarkable susceptibility to infection, with death due to infection within days to weeks ofbirth, even for mice in specic pathogen-free environments and on maintenance antibiotics (19,20). Complementing these loss-of-function studies, increasing NF-B activity in the lungs causesinammatory injury (18), consistent with roles in antimicrobial resistance pathways that are tissuedamaging. Mutations of upstream signaling intermediates that activate RelA, including MyD88,IRAK-4, and IKK, predispose to infections with bacterial respiratory pathogens in humans andin mice (21, 22). In short, whole-organism deciency of canonical NF-B signaling is profoundlyimmunosuppressive. RelAmutation in subsets of cells rather than in the whole organism can causesignicant phenotypes during pneumonia, as discussed below, revealing unique cell roles in resis-tance. The phenotypes of cell-specic RelA (or IKK orMyD88) mutations are milder than when

www.annualreviews.org Dynamics of Lung Defense in Pneumonia 409

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


NF-B signaling is targeted throughout the organism.One reasonmay be thatNF-B contributesto expression of the same protein from diverse cell types, continuing even when select cells cannotexpress it. In addition, there are cell-specic roles that depend uponNF-B; a well-established ex-ample is E-selectin from endothelial cells. However, no cell-specic roles are essential to all innateimmunity. For these reasons, widespread deletion of canonical NF-B signaling is consistentlyfar more detrimental than its targeted removal during pneumonia. Optimal immune resistanceagainst bacteria in the lung requires coordinated innate immune activities from a great number ofvery different cell types, involving pathways of cellular redundancy and cellular specialization.

Alveolar Macrophage Roles in Pneumonia Resistance

Alveolar macrophages are professional phagocytes on the apical epithelial surface in the distallung. They patrol these surfaces and ingest debris or other materials that are inhaled or otherwisedeposited there. Alveolar macrophages avidly consume even unopsonized materials, which theydispose of by internal dissolution and/or physical removal after accessing the mucociliary esca-lator. The ingestion of inert particles does not trigger inammatory responses from these cells,due to homeostatic mechanisms curbing baseline responsiveness (23). However, when these cellsrecognize pathogens, they produce alarm cytokines such as TNF-, IL-1, and IL-1. The rstburst of these cytokines during pneumonia is from alveolar macrophages and subsequently trig-gers rapid and coordinated responses to local infection (24). These alveolar macrophage cytokinesenhance immune resistance by alerting epithelial cells, endothelial cells, neutrophils, hepatocytes,and other cells to pathogen presence in the lung (20, 2528). When macrophages are decient inRelA, cytokine expression and neutrophil recruitment are delayed, and pneumococcal growth issustained (24). These functions of alveolar macrophages as sentinel cells are essential to rapid andeffective immune resistance during lung infection (Figure 2).

Typically, alveolar macrophages develop neonatally, proliferate locally, and live for many yearsas a stable population that does not rely on replacement by blood-borne precursors (29, 30). Alve-olar macrophages can survive the stresses of acute inammation and remain present followingresolution; whereas newly recruited phagocytes are eliminated, the original alveolar macrophagespersist (31). However, there are clear examples of alveolar macrophages dying during lung infec-tion, which has signicant consequences for immune resistance.

In murine models of pneumococcal pneumonia as well as in interactions of cultured cells withpneumococcus, alveolar macrophages can be driven to die by apoptosis (32). This outcome isinuenced by bacterial burden per macrophage, host factors such as opsonins and macrophageMcl-1, and bacterial factors such as toxins and capsular polysaccharides (33). Apoptotic alveolarmacrophage death facilitates the killing of internalized pneumococci (32, 33). Consistent with thispostulated pathway of protection, TRAIL is a cytokine that induces macrophage apoptosis, andTRAIL-decient mice have decreasedmacrophage apoptosis and increased bacterial burdens dur-ing pneumococcal pneumonia (34). Thus, the apoptotic death of alveolar macrophages enhancesimmune resistance during pneumococcal pneumonia (Figure 2).

In contrast, alveolar macrophage death by other pathways enhances microbial growth. Forexample, during Pseudomonas aeruginosa pneumonia, pyroptotic pathways are activated, and di-minishing pyroptotic pathways by diverse mechanisms consistently decreases bacterial burdensand diminishes inammatory injury (35). Although roles of alveolar macrophages per se and di-rect connections between pyroptosis and bacterial killing were not investigated, these studiessupport the emerging concept that alveolar macrophage death by pyroptosis may be detrimentalto immune resistance of the lungs. Similarly, during pneumococcal pneumonia, chitinase 3-like1 (Chi3l1) is essential (36). Chi3l1 prevents macrophage pyroptosis and enhances the killing of

410 Quinton Mizgerd

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


Pyroptosis,necroptosisPyroptosis,necroptosisPyroptosis,necroptosis

Infectionand injury

SentinelSentinelSentinel

Antibacterial affector

Phagocytosis,apoptosis



Antibacterialeffector

Proresolution Anti-inflammation

Alveolarmacrophage

Alveolarmacrophage

AlarmAlarmAlarm

EfferocytosisEfferocytosisEfferocytosisGap

junctionsGap

junctionsGap

junctions

Figure 2Roles of alveolar macrophages in resistance and resilience during pneumonia. As sentinel cells, alveolarmacrophages sound the initial alarm and are essential to the rapid activation of other cells, the recruitment ofneutrophils, and the killing of bacteria. In addition, alveolar macrophages are effectors of antibacterialresistance, capable of killing ingested bacteria, especially when undergoing apoptosis. The apoptosis of othercells in the lung stimulates alveolar macrophage efferocytosis, which eliminates dying leukocytes, preventstheir release of danger signals in the lungs, and switches macrophage phenotypes to producing anti-inammatory and proresolving signals. Select subsets of alveolar macrophages become nonmotile and adhereto the epithelium via gap junctions, through which these macrophages transmit Ca2+ waves that dampeninammatory signaling. However, when nonapoptotic pathways of cell death are triggered by microbialvirulence factors, alveolar macrophages become poor bacteria killers and release powerful proinammatorysignals that can exacerbate lung injury.

internalized bacteria, whichmay be causally related and applicable to alveolar macrophages duringpneumonia (36). Necroptosis is another pathway of cell death and (to our knowledge) has yet to beexamined in the context of pneumonia. Microbial factors that directly induce alveolar macrophagenecrosis, such as pneumolysin from pneumococcus or PB1-F2 from inuenza virus, can promoterespiratory infection, perhaps via that mechanism (37, 38). Autophagy pathways are involved inlung infections (39) and may help direct these coordinated macrophage resistance processes dur-ing pneumonia. Autophagy diminishes pyroptotic cell death in Legionella-infected macrophages(40) and enhances macrophage killing of ingested P. aeruginosa (41) and Candida albicans (42).Lines of evidence converge to suggest that alveolar macrophage death by nonapoptotic routescompromises immune resistance.

Lung Epithelial Cell Roles in Pneumonia Resistance

Forming the cellular surface of the respiratory tract, the epithelium helps combat respiratory in-fection. Constitutive functions of epithelial cells have well-described resistance functions, such asthose involving the mucociliary escalator (43, 44) and surfactant proteins A and D (45). However,


Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


inducible epithelial responses that contribute to immune resistance have been more difcult todiscern. Multiple studies demonstrate epithelial cell responses as important, including investiga-tions showing diminished pulmonary innate immunity after epithelial cellspecic interruptionsof canonical NF-B signaling (17). These loss-of-function studies are complemented by a gain-of-function approach involving a CC10-driven transgene; whereas P. aeruginosa grows inexorablyin lungs of MyD88/ mice, P. aeruginosa is effectively killed in lungs of MyD88-decient micewith MyD88 transgenically expressed in airway epithelial cells (46). Thus, MyD88 only in epithe-lial cells confers host defense to otherwise highly susceptible MyD88-decient mice. Althoughepithelial cell responses are clearly crucial to pneumonia outcome, their precise roles in resistanceare unknown.

Epithelial cells respond to respiratory infection with the production of diverse bactericidal orbacteriostatic compounds. In our opinions, none of these have been demonstrated to individu-ally exert especially profound effects during infection. -Defensin antimicrobial proteins can beinduced in cultured respiratory epithelial cells, but there is scant evidence for -defensin induc-tion during pneumonia or for contributions of -defensins to integrated pulmonary resistance.The deciency of murine -defensin 1 was demonstrated to signicantly exacerbate Haemophilusinuenzae infection (47), but little else beyond this single decade-old study implicates this familyof antimicrobial proteins in integrated resistance during pneumonia. In contrast to defensins, thechemokine CCL20 is consistently and strongly induced in epithelial cells of infected lungs (48,49), and CCL20 has -defensin-like antimicrobial activities in vitro (50). This nding suggeststhat epithelial cellderived CCL20 may be an antimicrobial protein in the air spaces, but thereis no direct evidence for this possibility to our knowledge. The chemical demands for CCL20santibacterial activity (including very low salt concentrations) temper enthusiasm for this otherwiseintriguing concept. Antimicrobial proteins in the cathelicidin, lysozyme, and lipocalin families in-crease and function in infected lungs, but their sources may more likely be leukocytes (5154).RegIII is a C-type lectin that is induced severalfold in lung infection, particularly prominently inepithelial cells, and antibodies against RegIII increase living Staphylococcus aureus 10-fold (55).However, the majority (>99.9%) of S. aureus are effectively eliminated within less than a day evenwith RegIII blockade, suggesting a modest scope. Splunc1, related to bactericidal/permeability-increasing protein, is an epithelium-derived protein whose expression increases severalfold duringpneumonia, and its deciency impairs resistance (56, 57). This resistance defect may be due toSplunc1 surface tension modulation that limits biolm formation by P. aeruginosa and Klebsiellapneumoniae (56, 57). Whether its induction (or instead its high basal levels) is critical to immuneresistance is uncertain. Analogous to neutrophils killing microbes with myeloperoxidase-derivedhypochlorite, epithelial cells can kill microbes via lactoperoxidase generation of hypothiocyanateand hypoiodous acid (58, 59). This role may be important to airway defense, but data so far arebased largely on cell culture and gain-of-function approaches, leaving the net signicance of ep-ithelial cellderived hypohalous acids in natural defenses unsettled. The activities of epithelialcells in driving hypohalous acid defense in vivo, including the dynamics of lactoperoxidase and itssubstrates (e.g., H2O2, SCN, and I) during infection, require further study.

Does the absence of evidence demonstrating individually vital roles for select epithelium-derived products suggestmodest effector roles for this cell type?We think not. Airway host defensecan be pharmacologically activated by bacterial products or their mimetics, which is astonishinglyprotective against a very wide variety of even highly pathogenic microbes (60). Activation of theepithelium is required for this protection, as demonstrated by the abrogation of this immuneresistance by the epithelium-specic, surfactant protein Cdriven targeting of MyD88 (61).That these improved defenses can be modeled in epithelial cell cultures (61) suggests that thisextraordinary protection involves antimicrobial effector functions of these cells, perhaps a

412 Quinton Mizgerd

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


combination of those described above and others yet to be discovered. In addition, the extraor-dinary defenses downstream of epithelial activation may also involve epithelial affector roles inimmune resistance.

Epithelial cellsmake a greatmany immunemediators during pneumonia, but very few inducibleimmune mediators have been demonstrated to be uniquely or nearly uniquely derived from thesecells. During pneumococcal pneumonia, CXCL5,GM-CSF, andCCL20 are specically epithelialin origin (48, 49), which may apply more broadly to other lung infections. CXCL5 is an ELR-positive CXC chemokine with complex roles during pneumonia. It can be essential to neutrophilrecruitment in settings of modest stimulation, but it conversely limits neutrophil recruitmentduring severe infection (62). GM-CSF is a growth factor with pleiotropic effects in myeloid celldynamics and is essential to maximal neutrophil recruitment in inamed lungs (63). During pneu-mococcal pneumonia, the interruption of canonical NF-B signaling throughout the epitheliumcompromises neutrophil recruitment, and this result can be reversed by increasing either CXCL5or GM-CSF, suggesting that lung concentrations for these two cytokines are limiting, NF-B de-pendent, epithelium derived, and essential to rapid neutrophil recruitment (48). In addition, GM-CSF from epithelial cells enhances the recruitment and function of CD103+ dendritic cells duringinuenza infection, facilitating the accumulation of inuenza-specic, IFN-secreting CD4+ andCD8+ T cells in the infected lung (64) and thus providing evidence for epithelial responses or-chestrating adaptive immunity. During respiratory syncytial virus (RSV) infection, CCL20 andits receptor CCR6 contribute to the recruitment of conventional dendritic cells to the lung, driv-ing immunopathology (65). In neutropenic mice, CCR6 enhances dendritic cell recruitment andantifungal lung defense (66), which may be downstream of CCL20. Potentially productive rolesof CCL20 generation by epithelial cells during lung infection remain uncertain. A fundamentalunderlying question is why epithelial cells should be specic sources for these or other immunesignals. Furthermore, the few epithelium-specic signals so far identied are likely not the only (ormost important) infection-induced products of this interface between the lungs and the externalenvironment, indicating that a more comprehensive description of epithelium-specic responsesin the pneumonic lung is needed.

Although the above studies emphasizeNF-Bsignaling, epithelial STAT3 functions in immuneresistance as well. Mice with Stat3 targeted in their lung epithelium have increased microbialburdens during diverse lung infections (18, 55, 67, 68). Signaling to epithelial STAT3 that drivespulmonary immune resistance comes from IL-6, IL-22, HVEM, and likely others (55, 63, 69, 70).Pathways downstream of epithelial STAT3 and driving immune resistance may constitute botheffector and affector roles. Althoughdemonstrably signicant, the epithelial products and pathwayscontributing to immune resistance downstream of STAT3 have yet to be compellingly dened.

Neutrophil Roles in Pneumonia Resistance

Neutropenia, whether purposefully induced in experiments or arising naturally from geneticor environmental causes, consistently predisposes to lung infection. Thus, neutrophils are anessential component of immune resistance to respiratory pathogens. Neutrophils are typicallyportrayed as professional antimicrobial effector cells, involving phagocytosis, degranulation, therespiratory burst, antimicrobial proteins, and neutrophil extracellular traps (NETs). The loss ofthese antimicrobial effector functions is almost certainly a major reason that neutropenic subjectsare prone to pneumonia.

Emerging evidence suggests that, in addition to their effector roles, neutrophils are also affectorcells. Neutrophils are important sources of immunemediators like cytokines and eicosanoids, withneutrophil-derived signals inuencing innate and adaptive immune responses (71). The concept of


Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


affector neutrophils is only beginning to be applied to the lung. In bioinformatics analyses of severeinuenza infections, a transcriptional signature associated with lethality emerges, and proling ofdistinct cell types within these lungs demonstrates that neutrophils are the source of the signature(72).Theneutrophil program involves a positive feedback loopbywhichneutrophils in the infectedlungs recruit and activate more neutrophils, with diminishing neutrophil recruitment capable ofpreventing mortality (72). There are likely many components to this positive feedback, includingan unexpected loop in which neutrophil-derived CXCL10 recruits and activates CXCR3+ neu-trophils in lung injury settings, including inuenza infection (73). Whereas those cases suggestthat neutrophil-driven neutrophil accumulation exacerbates immunopathology during severe lunginfection, other settings reveal protective resistance roles for affector neutrophils. For example,during pneumococcal pneumonia in mice, IFN is essential to maximal immune resistance, andthe sole source of IFN in these lungs is recruited neutrophils (74). This IFN promotes antibac-terial NETs (74), again emphasizing neutrophil-to-neutrophil signaling. Neutrophils also signalto other cells during pneumonia. As mentioned above, TRAIL stimulates alveolar macrophageapoptosis and is essential to effective host defense against pneumococcus (34). The primary sourceof TRAIL during pneumonia is neutrophils, and depletion of neutrophils results in decreasedTRAIL and less alveolar macrophage apoptosis (34). Because alveolar macrophage apoptosis isan antibacterial effector pathway (Figure 2), this neutrophil-derived paracrine signal enhancesresistance in the lung. Finally, affector roles of neutrophils outside the lungs may also help ghtrespiratory pathogens. Neutrophils in the marginal zone of the spleen function as B helper cellsby elaborating cytokines like BAFF, APRIL, and IL-21 that facilitate the development of antibod-ies against T cellindependent antigens (75). Consequently, neutropenic patients have decreasedantibodies against respiratory pathogens such as pneumococcus, P. aeruginosa, and Escherichia coli(75). Thus, affector neutrophils inuence lung infection in diverse fashions. Little is known abouttranscriptional regulation in neutrophils; where, when, and how neutrophil affector functionsinuence resistance to respiratory pathogens must be better dened.

Hepatocytes as a Source of Endocrine Immune Resistance

Not all cells mediating resistance against respiratory infection are in the lung. The immune systemis integrated across organs, and innate immune resistance against respiratory pathogens requirescoordinated efforts of cells in the bonemarrow, spleen, lymph nodes, gastrointestinal tract, adiposetissue, brain, andmore.The livermobilizes an impressive armament of immunomodulatory agents,which it secretes directly into the blood to serve endocrine innate immune functions. These rapidchanges in blood plasma constituents form the acute phase response, rst discovered in pneumoniapatients (76) and now recognized to follow virtually any form of physiological duress. Dozens ofacute phase proteins are linked to a variety of immunomodulatory and tissue-protective functions(77). Changes in acute phase proteins are biomarkers in diseases such as pneumonia. However,the net functional signicance of these acute changes in plasma components remains remarkablyspeculative.

Intrapulmonary delivery of bacteria or bacterial products elicits a rapid and robust acute phaseresponse (25, 37, 78, 79). The liver alters expression of more than a thousand genes during pneu-mococcal pneumonia (79). Hence, lung infection and host signals of pulmonary origin recalibratethe hepatic transcriptome in a lung-liver axis. During bacterial pneumonia, these liver-activatingsignals include IL-6, TNF-, IL-1, and IL-1 (25). Genetic deletion of IL-6 impairs liver acutephase protein expression and ablates Stat3 activation (25). RelA is also activated in the liver duringpneumonia, but activation of this transcription factor depends instead on TNF- and IL-1 (25,80). As in the case of IL-6, the interruption of TNF and IL-1 signaling diminishes hepatic acute

414 Quinton Mizgerd

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


phase protein induction (25). These cytokines are critical during pneumonia (17), and the liver isa conduit through which these cytokines exert roles in resistance.

Determining the direct inuence of hepatocyte activation on pneumonia outcomes requiresan effective and precise way of severing the lung-liver axis. Because both Stat3 and RelA wereimplicated in acute phase biology, we targeted them in hepatocytes (79). Simultaneous mutationof both Stat3 and Rela, but not mutation of either alone, ablates the hepatic transcriptional re-sponse to pneumococcal pneumonia (79). This hepatocyte-specic deciency of both Stat3 andRelA prevents all changes in the plasma proteins that were measured (79), revealing that livertranscription is responsible for these humoral events, with similar effects on hepatic acute phaseprotein expression observed for gram-negative pneumonia and diverse other inammatory chal-lenges (79). Mice with no hepatic acute phase responses due to targeting of Stat3 plus RelA havemore severe infections, including worse bacteremia during pneumococcal pneumonia (79). Acutephase remodeling of blood plasma enhances opsonization of blood-borne pneumococcus andphagocytosis by macrophages (79), demonstrating that one function of the hepatic acute phaseresponse is to provide a vascular shield against disseminated infection.

Although it is clear that the lung-liver axis is both present and relevant, the overall impactof hepatocyte activity during pneumonia is poorly dened. A prevailing question centers on theidentity of liver-derived products inuencing pneumonia outcomes. Changes in short pentraxinssuch as serum amyloid P (particularly dynamic inmice) orC-reactive protein (particularly dynamicin humans) may contribute, as these are in effect functional equivalents to antibody (81) andare required for bacterial opsonization and resistance during pneumococcal pneumonia in mice(82). Other known acute phase proteins, such as lipopolysaccharide (LPS)-binding protein, serumamyloid A, and complement, affect immune resistance and pulmonary inammation. Yet, formost of these proteins, the primary cellular sources (hepatocyte or other) and dynamics (rolesof basal levels or changes in expression) are yet to be discriminated during pneumonia. The netcontribution of these and other acute phase proteins is likely attributable to integrated changesin a wide array of mediators such that aiming to identify the most important factor(s) may beof limited signicance, if not impossible. An additional but tremendously important layer ofcomplexity related to the lung-liver axis is the fact that secreted acute phase proteins representonly a fraction of the many transcriptional changes observed in livers during pneumonia; othergene expression changes play additional important roles (37, 78, 79). For instance, liver responsesduring pneumococcal pneumonia include enrichment for genes linked to cholesterol biosynthesis(37), and the plasma increases in cholesterol during the acute phase response lead to its increasein the infected air spaces, to inactivation of the cytotoxin pneumolysin, and to diminished alveolarmacrophage necrosis (37). Many questions remain about how hepatic transcriptional activitiesinuence immune resistance, including effects on leukocytes and lung cells and their effector andaffector roles during infection.

RESILIENCE: TISSUE-PROTECTIVE PATHWAYSCOUNTERING LUNG INJURY

Immune resistance can be as dangerous as the microbes activating it. Tissue resilience balancesthe physiological damage from microbes and immune resistance pathways (11, 12). The signalsgoverning resilience in mammals are more obscure than those promoting resistance, representingan important direction for researchers interested in the physiology of infection. During pneumo-nia, inadequate tissue resilience promotes lung injury. Pneumonia is the most common cause ofacute respiratory distress syndrome (ARDS), with current mortality levels of 2030% accountingfor approximately 200,000 deaths annually in the United States (83). A better understanding of


Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


resilience mechanisms during pneumonia will help elucidate pathways that break down in patientswith or at risk for ARDS and that are potentially targetable for therapeutic, prognostic, and/ordiagnostic purposes.

Inducible Tissue Resilience Mediated by STAT3

Essential roles for STAT3 are evident in patients with hyper-IgE syndrome (HIES), formerlyknown as Jobs syndrome (84). The disease is caused by a dominant negative mutation in theSTAT3 gene, resulting in approximately 25% of normal STAT3 activity in the cells of patientsheterozygous for the mutation. HIES patients suffer from recurrent lung infections, beginning ininfancy and continuing throughout their lives. Most HIES patients die prematurely from pneu-monia and its consequences (85), likely due to myriad essential roles of STAT3 in both resistanceand resilience (Figure 3). As noted above, STAT3 in lung epithelial cells and in hepatocytes con-tributes to immune resistance. In addition, HIES patients have defective development of Th17cells (86), discussed below as an important resistance mechanism involved in immunological re-modeling. Roles of STAT3 in tissue resilience are evident as well. Cells from these patients haveimpaired responses to the anti-inammatory cytokine IL-10 (87). HIES patients universally de-velop large pneumatocoeles, often requiring surgery, reecting an abrogated lung repair processand extraordinarily dysfunctional tissue resilience (84). STAT3 contributes to tissue resilience in

STAT3STAT3

Acute phaseresponse

CD4+ T cellsCD4+ T cells

Th17 cytokines

Antimicrobialproteins

Cytoprotection, barrier integrity,migration, proliferation, stemness

MacrophagesMacrophages

Anti-inflammation

Hepatocytes Hepatocytes

Epithelial cellsEpithelial cells

Epithelial cellsEpithelial cellsIL-6

IL-6

IL-10IL-22LIF

IL-22

Figure 3The STAT3 transcription factor facilitates diverse processes paramount to pneumonia biology both insideand outside of the lungs. The indicated outcomes represent consequences of STAT3 activity downstream ofIL-6, leukemia inhibitory factor (LIF), IL-22, and IL-10 in select cell types during pneumonia. Theseoutcomes are critical determinants of immune resistance (antimicrobial proteins, acute phase response, Th17cytokines), tissue resilience (anti-inammatory signals, epithelial preservation, acute phase response), andimmune remodeling (Th17 cytokines). Pathways shown are those highlighted in the review and reect only afraction of the known roles of STAT3 that may be relevant to pneumonia.

416 Quinton Mizgerd

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


many ways, including the promotion of multipotency, proliferation, and migration as well as theprevention of apoptosis and other cell death pathways (18).

Lung Stat3 activation is characteristic of the acute pulmonary inammation elicited by hyper-oxia, ozone, immune complexes, LPS, viruses, or bacteria (18). Lung epitheliumspecic targetingconsistently supports a role for Stat3 in tissue resilience. Stat3 mutation in alveolar and/or air-way epithelium exacerbates lung injury across a wide variety of stimuli tested, including LPS,hyperoxia, naphthalene, and adenovirus (67, 8890). In some cases, lung injury has been linked todefective expression of antiapoptotic gene programs due to Stat3 deciency, althoughmechanismsdownstream of Stat3 are complex, multifactorial, and typically not well-dened (67, 8890). Dur-ing E. coli pneumonia, epithelial Stat3 is required for tissue resilience, as demonstrated by severealveolar edema in infected mice with Stat3 mutations in those cells (68). This tissue resiliencedefect seems the likely cause of excess pathophysiology in these mice because bacteria get effec-tively cleared despite compromised immune resistance (68). Complementing the STAT3 loss offunction in mouse studies and HIES patients, transgenic Stat3 gain of function in lung epithelialcells can protect against acute lung injury (91) but also results in chronic lung diseases such asadenocarcinoma (92).

Many factorsmay activate STAT3 in pneumonic lungs, and IL-6 is only partly responsible (93).Using a bioassay comparing air-space cytokine activities, we found that leukemia inhibitory factor(LIF) is even more prominent than IL-6 or any other cytokine in the IL-6 family in activatingepithelial Stat3 (68). LIF is a pleiotropic cytokine most widely appreciated for its capacity topreserve the totipotency of embryonic stem cells, suggesting potential roles in tissue regenerationand repair. Other known functions of LIF involve fertility, development, and hematopoiesis. LIFis present at elevated concentrations in pleural effusions (94) and bronchoalveolar lavage uidcollected from ARDS patients (95). A rare but severe disease, Stuve-Wiedemann syndrome, iscaused by null mutations in the LIF receptor (96). Respiratory distress represents one of severaldening characteristics of Stuve-Wiedemann syndrome, which typically results inmortality withinthe rst few months of life. During E. coli pneumonia in mice, LIF blockade results in devastatinglung injury that is independent of resistance signals like neutrophilia, proinammatory cytokines,and bacterial clearance (97). LIF potently activates Stat3 in airway and alveolar epithelial cells ofmice, and transcriptional proling of pneumonic lungs with LIF blockade reveals an enrichmentof genes belonging to many functional categories related to tissue resilience (e.g., cell death, cellcycle, and energy production) (97). These results suggest that LIF activation of Stat3 in epithelialcells helps preserve barrier integrity and function during infection (97). Constructing mechanisticpathways will require further knowledge about the sources, targets, and direct consequences ofLIF and STAT3 signaling during pneumonia.

Lung Epithelial Cell Roles in Pneumonia Resilience

Epithelial cells have multiple functions providing tissue resilience during pneumonia. Epithelialbarrier integrity limits lung injury by preventing uid access to the air spaces, which is dependentupon regulated epithelial cell tight junctions (98). During pneumonia, IL-22 stimulates resilienceby enhancing this barrier integrity (99). Epithelial cells further counter air-space edema accumula-tion by effectively pumping uid out of the lumen viaNa+-dependent transport, which is enhancedby endogenous epinephrine and glucocorticoids (98). As discussed above, Stat3 activation in theepithelium, by LIF and other factors, is cytoprotective and critical to limiting lung injury (67, 68,8890, 97). When epithelial cells die in the infected lung, tissue resilience demands their rapid re-placement via carefully coordinated proliferation and differentiation activities of epithelial and/orprogenitor cells. Epithelial cellbased repair processes implicated during lung infection include


Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


actions of IL-22 and Stat3 (100, 101), -catenin (102), FOXM1 (103), and p63 (104). Such re-generative pathways in the lung extend beyond epithelial cells to include multipotent stem cells(105), an emerging area with promise for repairing lungs injured by infection.

Mucus is a constitutively expressed epithelial product serving as a platform for eliminating mi-crobes from the airways via mucociliary clearance (44). Enhanced mucus production is triggeredby airway infection but is temporally associated with the resolution stages rather than with earlyor peak microbial activity. The exaggerated mucus is sustained long past the point at which it canproductively benet resistance, suggesting that mucus hyperproduction is more closely related toresilience. In support of this, evidence connects mucus hyperproduction to anti-inammatory ef-fects. First, the biosynthetic pathways ofmucusmetaplasia have direct anti-inammatory signalingactivities. For example, the SPDEF transcription factor denitive for mucus metaplasia inhibitsMyD88 and TRIF and the activation of NF-B in those mucus-elaborating epithelial cells, andoverexpression of this transcription factor decreases neutrophil recruitment and compromisesantibacterial defense in the mouse lung (106). Analogously, the FOXA3 transcription factor en-hances mucus production and simultaneously suppresses expression of inammatory and immuneresistance genes (107). Second, mucins themselves are anti-inammatory. This fact is especiallywell established for the membrane-bound mucin MUC1. MUC1 suppresses epithelial NF-B ac-tivation in an autocrine fashion by interrupting signaling from Toll-like receptors (108). DuringP. aeruginosa pneumonia,MUC1 expression peaks after>99.9%of bacteria are already eliminated,remains elevated long past any detection of live microbes, and is essential to the rapid resolutionof pulmonary inammation (108, 109). Mucins can also be paracrine anti-inammatory signals,as elegantly demonstrated in the gastrointestinal tract, where MUC2 is an immunoregulatoryagent stimulating anti-inammatory pathways in dendritic cells through a novel, multicomponentreceptor complex triggering the -catenin pathway (110). Together, the kinetics plus functionaldata strongly suggest that mucus hyperproduction triggered by lung infection functions primarilyas an anti-inammatory and proresolution tissue resilience program.

Alveolar Macrophage Roles in Pneumonia Resilience

Alveolar macrophages can be directed away from their sentinel alarm states (Figure 2) to in-stead actively curb inammation and promote tissue repair. Environmental cues can push alveolarmacrophages toward an M2 alternatively activated macrophage state in which they generate fac-tors like IL-10 and IL-1RA (23, 111). The M2 state has been observed in the resolution stages ofacute respiratory infections by P. aeruginosa (112), S. aureus (113), or inuenza virus (23). Consen-sus is yet to emerge on functional signicance or if, when, and how alveolar macrophages polarizetoward M2-like phenotypes with lung infections (23, 111). Intravital microscopy has recently re-vealed that, following an intrapulmonary challenge with LPS or P. aeruginosa, a fraction of alveolarmacrophages become immobilized on the alveolar surface (114). These sessile macrophages formconnexin 43containing gap junctions with the underlying epithelium, through which they coor-dinate Ca2+ signaling. Ca2+-dependent Akt activation reduces alveolar neutrophilia and cytokineinduction in wild-type mice, in contrast to the case for mice in which intercellular gap junctionsare eliminated by mutation of connexin 43 in either macrophages or epithelial cells (114). Thispresents a novel perspective in which a subset of alveolar macrophages is nonmotile, connectedphysically and chemically with the epithelium, and primarily anti-inammatory (Figure 2). Ourunderstanding of these sessile cells is in its infancy, and their development, phenotype, and functionmerit substantial further exploration.

As implied by their original moniker dust cells, alveolar macrophages are waste-collecting cellsin the air spaces.This is also true in the resolution stages of pneumonia, when alveolarmacrophages

418 Quinton Mizgerd

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


help dispose of the dead and dying inammatory cells that were recruited for immune resistance.The phagocytosis of apoptotic cells by macrophages, known as efferocytosis, eliminates effeteleukocytes, prevents the necrotic release of intracellular danger signals, and actively suppressesinammation (Figure 2). Efferocytosis reprograms macrophages to diminish expression of proin-ammatory cytokines and to promote expression of anti-inammatory cytokines, and efferocytosisby alveolar macrophages induces TGF to enhance resilience during acute pulmonary inamma-tion (115). Efferocytosis occurs in concert with the induction of proresolving lipid mediators suchas lipoxins, resolvins, protectins, and maresins (116). These mediators form a positive feedbackloop in which efferocytosis stimulates the generation of lipid mediators that stimulate efferocy-tosis, with alveolar macrophages being both a source and a site of action for these lipids (116).Difculties in inhibiting the endogenous generation of or signaling by specic members of thisproresolution lipid family has complicated the dissection of their natural roles during pneumo-nia, but they are made in the injured lung and have proresolving and anti-inammatory resilienceproperties (116). Suggesting therapeutic potential, administration of exogenous proresolving lipidmediators improves lung injury in mouse models (116).

As emphasized above, alveolar macrophage sentinel functions are essential to effective de-fense, so tissue resilience pathways that blunt alveolar macrophage responses may be delete-rious by fostering microbial growth. Lipocalin 2 (Lcn2), which enhances immune resistanceagainst siderophore-dependent bacteria like K. pneumoniae (53), is also an alveolar macrophagedeactivating factor via an autocrine IL-10 and STAT3 loop (54). During pneumonia caused bypneumococcus (which does not express siderophores), Lcn2 is abundant in the patients air spaces,highLcn2 levels correlatewithworse patient outcomes, andLcn2-decientmice have far improveddefenses (54), altogether suggesting that Lcn2-deactivated alveolar macrophages are counterpro-ductive in such infections. Inactivation of alveolar macrophages by other mechanisms, such assepsis-induced IRAK-M expression (117), is also deleterious for compromising immune resis-tance. Just as too much activity in immune resistance pathways fosters lung injury, too muchactivity in tissue resilience pathways can exacerbate lung infection (Figure 1).

Lymphocyte Roles in Pneumonia Resilience

Lymphocytes are professional immunoregulators and sources of resilience mediators like TGF,IL-10, and IL-22. After a bolus of LPS in the lungs, regulatory CD4+ T cells expressing CD25and FOXP3 (Tregs) accumulate in the lungs during resolution, and these Tregs are sufcientand necessary to limit lung injury through TGF expression (118). Similarly, CD8+ T cells havebeen shown to provide resilience in response to inuenza and RSV infections, as sources of IL-10,which curbs lung injury (119); such roles of CD8+ T cells outside of viral infection remain lesscertain. NK cells are sources of IL-22 and its contributions to resilience during K. pneumoniaeor inuenza pneumonia (100, 120). A novel set of tissue-protective lymphocytes was identiedduring inuenza infection as a population of lineage-negative CD90+CD25+ innate lymphoidcells that promote resilience through expression of the EGF family member amphiregulin (121).Amphiregulin was also protective when provided exogenously in a model of inuenza-induceddepressed tissue resilience againstLegionella pneumonia (122). Roles of lymphocytes in pneumoniarequire further study, as emphasized below.

Roles of Other Cells in Resilience During Pneumonia

Tissue resilience is also observed in other tissues and derived from other cells. The pronouncedtranscriptional responses of hepatocytes described above places physiological stress on the liver.


Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


Stat3-mediated gene expression helps mitigate this stress, inducing unfolded protein responsegenes and secretory protein genes to counter endoplasmic reticulum stress in hepatocytes (78).Although canonical NF-B signaling is especially important in resistance, it has roles in resilienceas well, particularly in the liver. RelA prevents death receptorinduced apoptosis, which is es-sential for preventing liver injury after a systemic high dose of TNF- or LPS challenge (123).Liver injury is not observed in mice with RelA mutated in their hepatocytes during pneumococcalpneumonia (79), but whether and when RelA-induced resilience protects the liver during lunginfection require more study. In addition to protecting the liver, the acute phase response involvesthe synthesis ofmany factors with tissue-protective properties, such as antiprotease and antioxidantproteins (77). These hepatic actionsmay help protect the lungs from injury during pneumonia, butthis is presently speculative. During systemic sepsis, gp130-dependent Stat3 activity in hepato-cytes is required for the mobilization and tissue accumulation of a myeloid-derived suppressor cell(MDSC) population generating anti-inammatory signals to prevent inammatory injury (124).Although the degree to which MDSCs rely on the lung-liver axis is unknown, a population ofMDSCs accumulates in the lungs during K. pneumoniae pneumonia; these cells can efferocytoseapoptotic neutrophils and synthesize IL-10, implicating them as local contributors to resilience(125). Inammatory monocyte macrophages are another myeloid source of recruited resilience.Following intrapulmonary challenges with either LPS or K. pneumoniae, exudate macrophagesare sources of IL-1RA, without which lung injury is exacerbated (126). And in a model in whichexposures to low doses of LPS protect mice from subsequent and otherwise lethal doses of LPS orP. aeruginosa, IL-10 is the protective factor and derived from recruited monocyte macrophages(127). Finally, the bone marrowderived mesenchymal stem cell can be a source of cell-mediatedtissue resilience and represents a promising therapeutic strategy. In the context of pneumonia,delivery of mesenchymal stem cells markedly diminishes acute lung injury in mouse models ofpneumonia (128) and in human models of injury to isolated and perfused lung preparations (129).The potential contribution of mesenchymal stem cells to therapeutic use exemplies the trans-lational importance of understanding whether and how resilience pathways can be calibrated inpneumonic lungs.

REMODELING: RESPONSES TO LUNG INFECTION DIFFERTHROUGHOUT A LIFETIME

Pneumonia over a Life Course

Pneumonia hospitalization rates plummet during early childhood, remain low through youngadulthood, and rise again in later years (Figure 4a). Alterations in resistance likely contribute toboth the early deceleration and the later acceleration of pneumonia rates (Figure 4b). For thosewith pneumonia, the risk of death steadily increases over the life course (Figure 4a), suggesting thatwithstanding the challenges of pneumonia becomes more difcult as we age, perhaps because ofdeclines in tissue resilience (Figure 4b).We propose that the combined decreases in both immuneresistance and tissue resilience are responsible for pneumonia being so excessively common andunacceptably severe among the elderly. The ways in which resistance and resilience vary overa lifetime are poorly understood and are an area in which new insights could have especiallysubstantial impacts.

Heterotypic Immune Protection in the Trough Period of Low Susceptibility

Even in people with deciencies of MyD88 or IRAK-4, severe infections with respiratorypathogens decrease dramatically by late childhood (21), revealing that protection involves factors

420 Quinton Mizgerd

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


0 20 40 60 80 100

200

400

600

800

1,000

2,000

3,000

4,000

5,000

0

2

4

6

8

10

12

Age (years)

Pneu

mon

ia h

ospi

taliz

atio

ns(p

er 1

00,0

00 U

S po

pula

tion

)

Pneumonia deaths

(percentage of those hospitalized)

a

0 20 40 60 80 100Age (years)

Hos

t fac

tors

Immune resistance

Tissue resilience

Overall protection

b

Figure 4Remodeling responses to pneumonia throughout the lifetime. (a) Effect of age on pneumonia in the United States, from 2007 to 2009.The red line shows age-stratied hospitalizations for pneumonia of any cause per 100,000 US population, reecting a U-shaped curvebetween birth and retirement ages, followed by a steeper incline to far greater hospitalization rates among the elderly (note break iny-axis at left). The blue line shows rates of in-hospital death related to pneumonia from any cause, reecting a steady increase beginningin early childhood and continuing throughout the ensuing years. The graph was constructed from data communicated by Grifn et al.(155), with ages plotted as the midpoint of each age range reported. (b) Conceptual framework portraying how changes in resistanceand resilience may be responsible for the effects of age on pneumonia (as in panel a). We propose that immune resistance increasesdramatically in childhood due to the development of heterotypic adaptive immunity and lung-resident memory against respiratorypathogens, which together protect younger adults but (we predict) wane in the elder years. We propose that tissue resilience declinesthroughout the lifetime, increasing pneumonia death rates even among those with strong resistance and then synergizing with thedecreasing resistance in the elder years to render pneumonia incidence and severity especially elevated at those ages. Overall protectionagainst pneumonia, plotted here as a simple sum of resistance plus resilience, plummets when both parameters of lung defensesimultaneously decrease. Panel b does not reect actual data but rather reects a conceptual framework that we constructed tocommunicate the paradigms spotlighted in this review.

other than the maturation of innate immunity. Patients with defects in adaptive immunity, as areseen in asplenia or AIDS, are very susceptible to pneumonia as adults. A considerable componentof adaptive immune protection against respiratory pathogens appears to involve heterotypicimmunity, pathways that are elicited by conserved epitopes within a species and provide effectivebut suboptimal protection (e.g., less than type-specic immunity within a serotype or strain).This is particularly well documented for inuenza. Both observational and experimental studiesdemonstrate that humans with preexisting memory T cells responsive to conserved inuenzaepitopes have less severe respiratory infection by inuenza viruses to which the subjects werepreviously naive (130, 131). Protective correlates include CD4+ and CD8+ memory T cells,IFN expressing and cytotoxic in both cases (130, 131). Mouse models reveal similar heterotypicprotection and activities from CD4+ and CD8+ cells during inuenza pneumonia (119, 132).Thus, naturally acquired heterotypic immune responses substantially limit the severity ofrespiratory infection by new strains of inuenza virus.

Heterotypic immunity is implicated for bacterial pneumonias as well. In mouse experiments,adjuvanted killed bacteria vaccines (for pneumococcus or K. pneumoniae) elicit heterotypic protec-tion against diverse serotypes of those bacteria, and this serotype-independent protection dependson Th17 cells (and neutrophils), but not on antibodies (133, 134). Similarly, nasal colonization ofmice with pneumococcus can lead to antibody-independent and Th17-dependent immune resis-tance (135, 136). Adults have memory T cells in their blood that respond to pneumococcal protein


Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


antigens with proliferation and IL-17 production (137), and pneumococcal exposure of the res-piratory tract increases Th17 cells in the bronchoalveolar lavage uid (138), suggesting naturallydeveloped heterotypic immune memory. Although not implicated in the above-described mousecolonization or vaccination experiments, heterotypic antibodies may also be protective in adulthumans. A peptide screening approach reveals human serum to contain antibodies against per-haps >140 different protein antigens of pneumococcus, some of which provide protection inmouse models of pneumonia (139). Thus, early-life exposures lead to memory CD4+ T cells andantibodies that provide heterotypic immune resistance against bacterial respiratory pathogens. Al-though less than optimal (e.g., compared with capsular polysaccharide-specic antibodies), theseheterotypic responses are an improvement over naive infections. Heterotypic memory Th17 cellsplus antibodies against conserved virulence factors may provide much of the adaptive immune re-sistance of the so-called troughperiod,which is characterized by lower susceptibility to pneumonia.

Lung-Resident Immune Cells and Protection from Pneumonia

Adult human lungs contain abundant lymphocytes, with memory CD4+ T cells especially promi-nent (140, 141). Most studies of adaptive immunity against respiratory pathogens involve lym-phocytes from the blood, mucosal surfaces (lavageates), or secondary lymphoid organs, but lung-resident lymphocytesmay be distinct.Mousemodels of pulmonary inuenza infection differentiatebetween two populations of memory CD4+ T cells: (a) those that circulate and are found in theblood and secondary lymphoid organs and (b) those that reside in the lung tissues instead and donot recirculate (142). The latter, resident memory T cells (TRM) from the lung, provide greaterprotection against inuenza infection (142); the underlying mechanisms are unknown. In humans,more of the T cells from lung tissue are responsive to inuenza than are T cells from the blood orskin (140), but little else is known about the antigen specicity of lung TRM. They show polyfunc-tionality after antigen-independent activation (140, 141), but almost nothing is appreciated aboutthe cytokine proles, skewing, or other activities of naturally stimulated lung TRM. In mice, lungTRM but not memory cells from secondary lymphoid organs express IFITM3, an antiviral proteinpermitting cell survival when the lung is infected by inuenza virus (143), indicating an adaptationto tissue residence. The specicities and activities of lung TRM are large and likely signicant gapsin our understanding of lung defense against respiratory pathogens.

Innate-like lymphocytes, including NKT cells (144), MAIT cells (145), -T cells (146), andNK cells (120), can also provide resistance against bacteria in the lungs. Roles of these cellsand how they change over the life course demand further study. Furthermore, it is not unusualfor lungs to develop ectopic tertiary lymphoid structures, particularly with chronic lung diseases(147), and the effect of these structures on pneumonia susceptibility deserves further attention.The animal models currently used to study pneumonia biology and pulmonary defenses typicallyfail to account for the complex relationships between lymphocytes and lungs observed in adulthumans. New model systems and thoughtful integration of human and animal experimentationwill be needed to generate insights into the specialized immune system of the lung and its rolesin protection against respiratory pathogens.

Resistance and Resilience in the Elderly

Pneumonias are exceptionally common and severe in the elderly (Figure 4a), whichwe attribute tocombined decreases in both resistance and resilience (Figure 4b).With immune resistancemecha-nisms preventing severe pneumonias in young adults only beginning to be understood, it is difcultto identify specic defects that occur with aging and that contribute to pneumonia susceptibility.

422 Quinton Mizgerd

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


Greater insights into resistance pathways responsible for decelerating pneumonias in childhoodandmaintaining the trough period of young adulthood are needed to rationally guide further stud-ies of the effects of aging on resistance. Although much is known about immunosenescence (148),little to date specically applies to heterotypic immunity against respiratory pathogens and none(to our knowledge) to lung-resident immune cells. Regarding tissue resilience, perhaps all organsof elderly individuals are less capable of withstanding stress, due to cellular senescence, telomereshortening, genome instability, epigenetic alterations, stem cell loss, and more (149151). Thelungs show signs of aging-induced changes that accelerate with comorbidities (152, 153), whichmay contribute to pneumonia in the elderly. Mechanisms behind the loss of tissue resilience inthe lung, and contributions to infection outcomes, are speculative. Supporting the concept thatdecreases in tissue resilience begin early (as in Figure 4b), children are less likely than adultsto develop acute lung injury in a variety of severe infections or other challenges (154). Scant ifany data directly demonstrate how declines in tissue resilience impact pneumonia biology, but suchdata could be important to understanding and preventing the increased pneumonia incidence andseverity in older individuals.

CONCLUSIONS

The public health crisis attributable to pneumonia is comparable to or worse than many diseasesthat garner greater attention. Pneumonia warrants more awareness by advocates and strongereffort by researchers. Elucidating the basic biological principles governing resistance, resilience,and their age-dependent remodeling will help to identify novel targets for diagnostic, prognos-tic, and therapeutic intervention in patients with or at risk for pneumonia. Imbalances amongthese processes that evolved to counter pressures of acute respiratory infection are paramountin shaping the pathogenesis of and susceptibility to many chronic lung diseases (4), includingCOPD, pulmonary brosis, asthma, and lung cancer. Continued insights into immune resistance,tissue resilience, and their remodeling will advance our ght against lung diseases directly and/orindirectly linked to respiratory infection.

DISCLOSURE STATEMENT

The authors are not aware of any afliations, memberships, funding, or nancial holdings thatmight be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

This work was funded in part by National Institutes of Health grants R01HL079392 ( J.P.M.),R01HL068153 ( J.P.M.), R01HL111449 (L.J.Q.), and R00HL092956 (L.J.Q.).

LITERATURE CITED

1. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, et al. 2012. Years lived with disability (YLDs)for 1160 sequelae of 289 diseases and injuries 19902010: a systematic analysis for the Global Burden ofDisease Study 2010. Lancet 380:216396

2. Armstrong GL, Conn LA, Pinner RW. 1999. Trends in infectious disease mortality in the United Statesduring the 20th century. JAMA 281:6166

3. Liu L, Johnson HL, Cousens S, Perin J, Scott S, et al. 2012. Global, regional, and national causes ofchild mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 379:215161


Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


4. Mizgerd JP. 2012. Respiratory infection and the impact of pulmonary immunity on lung health anddisease. Am. J. Respir. Crit. Care Med. 186:82429

5. Curns AT,HolmanRC, Sejvar JJ,OwingsMF, Schonberger LB. 2005. Infectious disease hospitalizationsamong older adults in the United States from 1990 through 2002. Arch. Intern. Med. 165:251420

6. FryAM, ShayDK,HolmanRC,CurnsAT,AndersonLJ. 2005.Trends in hospitalizations for pneumoniaamong persons aged 65 years or older in the United States, 19882002. JAMA 294:271219

7. Mizgerd JP. 2006. Lung infectiona public health priority. PLOS Med. 3:e768. Van Eeden S, Leipsic J, Paul Man SF, Sin DD. 2012. The relationship between lung inammation and

cardiovascular disease. Am. J. Respir. Crit. Care Med. 186:11169. Edmond K, Scott S, Korczak V, Ward C, Sanderson C, et al. 2012. Long term sequelae from childhood

pneumonia; systematic review and meta-analysis. PLOS ONE 7:e3123910. Shah FA, Pike F, Alvarez K, Angus D, Newman AB, et al. 2013. Bidirectional relationship between

cognitive function and pneumonia. Am. J. Respir. Crit. Care Med. 188:5869211. Ayres JS, Schneider DS. 2012. Tolerance of infections. Annu. Rev. Immunol. 30:2719412. MedzhitovR, SchneiderDS, SoaresMP. 2012.Disease tolerance as a defense strategy.Science 335:9364113. Cilloniz C, Ewig S, Polverino E,MarcosMA, Esquinas C, et al. 2011.Microbial aetiology of community-

acquired pneumonia and its relation to severity. Thorax 66:3404614. Jones RN. 2010.Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated

bacterial pneumonia. Clin. Infect. Dis. 51(Suppl. 1):818715. Mizgerd JP, Skerrett SJ. 2008. Animal models of human pneumonia. Am. J. Physiol. Lung Cell. Mol.

Physiol. 294:L3879816. Matute-Bello G, Frevert CW, Martin TR. 2008. Animal models of acute lung injury. Am. J. Physiol.

Lung Cell. Mol. Physiol. 295:L3799917. Mizgerd JP. 2008. Acute lower respiratory tract infection. N. Engl. J. Med. 358:7162718. Quinton LJ, Mizgerd JP. 2011. NF-B and STAT3 signaling hubs for lung innate immunity. Cell Tissue

Res. 343:1536519. Alcamo E, Mizgerd JP, Horwitz BH, Bronson R, Beg AA, et al. 2001. Targeted mutation of TNF

receptor I rescues theRelA-decientmouse and reveals a critical role forNF-B in leukocyte recruitment.J. Immunol. 167:1592600

20. Quinton LJ, Jones MR, Simms BT, Kogan MS, Robson BE, et al. 2007. Functions and regulation ofNF-B RelA during pneumococcal pneumonia. J. Immunol. 178:1896903

21. Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, et al. 2010. Clinical features and outcomeof patients with IRAK-4 and MyD88 deciency. Medicine 89:40325

22. Pannicke U, Baumann B, Fuchs S, Henneke P, Rensing-Ehl A, et al. 2013. Deciency of innate andacquired immunity caused by an IKBKB mutation. N. Engl. J. Med. 369:250414

23. Hussell T, Bell TJ. 2014. Alveolar macrophages: plasticity in a tissue-specic context.Nat. Rev. Immunol.14:8193

24. Pittet LA, Quinton LJ, Yamamoto K, Robson BE, Ferrari JD, et al. 2011. Earliest innate immuneresponses require macrophage RelA during pneumococcal pneumonia. Am. J. Respir. Cell Mol. Biol.45:57381

25. Quinton LJ, Jones MR, Robson BE, Mizgerd JP. 2009. Mechanisms of the hepatic acute-phase responseduring bacterial pneumonia. Infect. Immun. 77:241726

26. Hess C, Herr C, Beisswenger C, Zakharkina T, Schmid RM, Bals R. 2010. Myeloid RelA regulatespulmonary host defense networks. Eur. Respir. J. 35:34352

27. Cakarova L, Marsh LM, Wilhelm J, Mayer K, Grimminger F, et al. 2009. Macrophage tumor necrosisfactor- induces epithelial expression of granulocytemacrophage colony-stimulating factor: impact onalveolar epithelial repair. Am. J. Respir. Crit. Care Med. 180:52132

28. MarriottHM,GascoyneKA,GowdaR,Geary I, NicklinMJ, et al. 2011. IL-1regulates CXCL8 releaseand inuences disease outcome in response to Streptococcus pneumoniae, dening intracellular cooperationbetween pulmonary epithelial cells and macrophages. Infect. Immun. 80:114049

29. Guilliams M, De Kleer I, Henri S, Post S, Vanhoutte L, et al. 2013. Alveolar macrophages develop fromfetal monocytes that differentiate into long-lived cells in the rst week of life via GM-CSF. J. Exp. Med.210:197792

424 Quinton Mizgerd

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


30. Murphy J, Summer R, Wilson AA, Kotton DN, Fine A. 2008. The prolonged life-span of alveolarmacrophages. Am. J. Respir. Cell Mol. Biol. 38:38085

31. Janssen WJ, Barthel L, Muldrow A, Oberley-Deegan RE, Kearns MT, et al. 2011. Fas determinesdifferential fates of resident and recruited macrophages during resolution of acute lung injury. Am. J.Respir. Crit. Care Med. 184:54760

32. Marriott HM, Bingle CD, Read RC, Braley KE, Kroemer G, et al. 2005. Dynamic changes in Mcl-1expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. J. Clin.Investig. 115:35968

33. Aberdein JD,Cole J, BewleyMA,MarriottHM,DockrellDH. 2013. Alveolarmacrophages in pulmonaryhost defencethe unrecognized role of apoptosis as a mechanism of intracellular bacterial killing. Clin.Exp. Immunol. 174:193202

34. Steinwede K, Henken S, Bohling J, Maus R, Ueberberg B, et al. 2012. TNF-related apoptosis-inducingligand (TRAIL) exerts therapeutic efcacy for the treatment of pneumococcal pneumonia in mice.J. Exp. Med. 209:193752

35. Cohen TS, Prince AS. 2013. Activation of inammasome signaling mediates pathology of acuteP. aeruginosa pneumonia. J. Clin. Investig. 123:163037

36. Dela Cruz CS, Liu W, He CH, Jacoby A, Gornitzky A, et al. 2012. Chitinase 3-like-1 promotes Strep-tococcus pneumoniae killing and augments host tolerance to lung antibacterial responses. Cell Host Microbe12:3446

37. Weber M, Lambeck S, Ding N, Henken S, Kohl M, et al. 2012. Hepatic induction of cholesterolbiosynthesis reects a remote adaptive response to pneumococcal pneumonia. FASEB J. 26:242436

38. Alymova IV, Samarasinghe A, Vogel P, Green AM, Weinlich R, McCullers JA. 2014. A novel cytotoxicsequence contributes to inuenza A viral protein PB1-F2 pathogenicity and predisposition to secondarybacterial infection. J. Virol. 88:50315

39. Nakahira K, Choi AM. 2013. Autophagy: a potential therapeutic target in lung diseases. Am. J. Physiol.Lung Cell. Mol. Physiol. 305:L93107

40. Byrne BG, Dubuisson JF, Joshi AD, Persson JJ, Swanson MS. 2013. Inammasome components coor-dinate autophagy and pyroptosis as macrophage responses to infection. MBio 4:e0062012

41. Yuan K, Huang C, Fox J, Laturnus D, Carlson E, et al. 2012. Autophagy plays an essential role in theclearance of Pseudomonas aeruginosa by alveolar macrophages. J. Cell Sci. 125:50715

42. Tam JM,MansourMK, KhanNS, SewardM, Puranam S, et al. 2014. Dectin-1-dependent LC3 recruit-ment to phagosomes enhances fungicidal activity in macrophages. J. Infect. Dis. 210:184454

43. KnowlesMR,Daniels LA, Davis SD, ZariwalaMA, LeighMW. 2013. Primary ciliary dyskinesia. Recentadvances in diagnostics, genetics, and characterization of clinical disease. Am. J. Respir. Crit. Care Med.188:91322

44. Roy MG, Livraghi-Butrico A, Fletcher AA, McElwee MM, Evans SE, et al. 2014. Muc5b is required forairway defence. Nature 505:41216

45. Wright JR. 2005. Immunoregulatory functions of surfactant proteins. Nat. Rev. Immunol. 5:586846. Mijares LA, Wangdi T, Sokol C, Homer R, Medzhitov R, Kazmierczak BI. 2011. Airway epithelial

MyD88 restores control of Pseudomonas aeruginosa murine infection via an IL-1-dependent pathway.J. Immunol. 186:708088

47. Moser C, Weiner DJ, Lysenko E, Bals R, Weiser JN, Wilson JM. 2002. -Defensin 1 contributes topulmonary innate immunity in mice. Infect. Immun. 70:306872

48. Yamamoto K, Ahyi AN, Pepper-Cunningham ZA, Ferrari JD, Wilson AA, et al. 2014. Roles of lungepithelium in neutrophil recruitment during pneumococcal pneumonia. Am. J. Respir. Cell Mol. Biol.50:25362

49. Yamamoto K, Ferrari JD, Cao Y, Ramirez MI, Jones MR, et al. 2012. Type I alveolar epithelial cellsmount innate immune responses during pneumococcal pneumonia. J. Immunol. 189:245059

50. Starner TD, Barker CK, Jia HP, Kang Y,McCray PB Jr. 2003. CCL20 is an inducible product of humanairway epithelia with innate immune properties. Am. J. Respir. Cell Mol. Biol. 29:62733

51. Kovach MA, Ballinger MN, Newstead MW, Zeng X, Bhan U, et al. 2012. Cathelicidin-related antimi-crobial peptide is required for effective lung mucosal immunity in Gram-negative bacterial pneumonia.J. Immunol. 189:30411


Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


52. Markart P, KorfhagenTR,WeaverTE, AkinbiHT. 2004.Mouse lysozymeM is important in pulmonaryhost defense against Klebsiella pneumoniae infection. Am. J. Respir. Crit. Care Med. 169:45458

53. Chan YR, Liu JS, Pociask DA, ZhengM,Mietzner TA, et al. 2009. Lipocalin 2 is required for pulmonaryhost defense against Klebsiella infection. J. Immunol. 182:494756

54. Warszawska JM, Gawish R, Sharif O, Sigel S, Doninger B, et al. 2013. Lipocalin 2 deactivatesmacrophages and worsens pneumococcal pneumonia outcomes. J. Clin. Investig. 123:336372

55. Choi SM, McAleer JP, Zheng M, Pociask DA, Kaplan MH, et al. 2013. Innate Stat3-mediated inductionof the antimicrobial protein Reg3 is required for host defense against MRSA pneumonia. J. Exp. Med.210:55161

56. Liu Y, Bartlett JA, Di ME, Bomberger JM, Chan YR, et al. 2013. SPLUNC1/BPIFA1 contributes topulmonary host defense against Klebsiella pneumoniae respiratory infection. Am. J. Pathol. 182:151931

57. Liu Y, Di ME, Chu HW, Liu X, Wang L, et al. 2013. Increased susceptibility to pulmonary Pseudomonasinfection in Splunc1 knockout mice. J. Immunol. 191:425968

58. Fischer AJ, Lennemann NJ, Krishnamurthy S, Pocza P, Durairaj L, et al. 2011. Enhancement of respi-ratory mucosal antiviral defenses by the oxidation of iodide. Am. J. Respir. Cell Mol. Biol. 45:87481

59. Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB Jr, et al. 2007. A novel host defense systemof airways is defective in cystic brosis. Am. J. Respir. Crit. Care Med. 175:17483

60. Evans SE, Xu Y, TuvimMJ,Dickey BF. 2010. Inducible innate resistance of lung epithelium to infection.Annu. Rev. Physiol. 72:41335

61. Cleaver JO, YouD,MichaudDR, Pruneda FA, JuarezMM, et al. 2014. Lung epithelial cells are essentialeffectors of inducible resistance to pneumonia. Mucosal Immunol. 7:7888

62. Mei J, Liu Y, Dai N, Favara M, Greene T, et al. 2010. CXCL5 regulates chemokine scavenging andpulmonary host defense to bacterial infection. Immunity 33:10617

63. Bozinovski S, Jones J, Beavitt SJ, Cook AD,Hamilton JA, AndersonGP. 2004. Innate immune responsestoLPS inmouse lung are suppressed and reversed by neutralization ofGM-CSF via repression ofTLR-4.Am. J. Physiol. Lung Cell. Mol. Physiol. 286:L87785

64. Unkel B, Hoegner K, Clausen BE, Lewe-Schlosser P, Bodner J, et al. 2012. Alveolar epithelial cellsorchestrate DC function in murine viral pneumonia. J. Clin. Investig. 122:365264

65. Kallal LE, Schaller MA, Lindell DM, Lira SA, Lukacs NW. 2010. CCL20/CCR6 blockade enhancesimmunity to RSV by impairing recruitment of DC. Eur. J. Immunol. 40:104252

66. Phadke AP, Akangire G, Park SJ, Lira SA, Mehrad B. 2007. The role of CC chemokine receptor 6 inhost defense in a model of invasive pulmonary aspergillosis. Am. J. Respir. Crit. Care Med. 175:116572

67. Matsuzaki Y, Xu Y, Ikegami M, Besnard V, Park KS, et al. 2006. Stat3 is required for cytoprotection ofthe respiratory epithelium during adenoviral infection. J. Immunol. 177:52737

68. Quinton LJ, Jones MR, Robson BE, Simms BT, Whitsett JA, Mizgerd JP. 2008. Alveolar epithelialSTAT3, IL-6 family cytokines, and host defense during Escherichia coli pneumonia. Am. J. Respir. CellMol. Biol. 38:699706

69. Laan M, Prause O, Miyamoto M, Sjostrand M, Hytonen AM, et al. 2003. A role of GM-CSF in theaccumulation of neutrophils in the airways caused by IL-17 and TNF-. Eur. Respir. J. 21:38793

70. Shui JW, Larange A, Kim G, Vela JL, Zahner S, et al. 2012. HVEM signalling at mucosal barriersprovides host defence against pathogenic bacteria. Nature 488:22225

71. Jaillon S, Galdiero MR, Del Prete D, Cassatella MA, Garlanda C, Mantovani A. 2013. Neutrophils ininnate and adaptive immunity. Semin. Immunopathol. 35:37794

72. Brandes M, Klauschen F, Kuchen S, Germain RN. 2013. A systems analysis identies a feedforwardinammatory circuit leading to lethal inuenza infection. Cell 154:197212

73. Ichikawa A, Kuba K, Morita M, Chida S, Tezuka H, et al. 2013. CXCL10-CXCR3 enhances the devel-opment of neutrophil-mediated fulminant lung injury of viral and nonviral origin. Am. J. Respir. Crit.Care Med. 187:6577

74. Yamada M, Gomez JC, Chugh PE, Lowell CA, Dinauer MC, et al. 2011. Interferon- production byneutrophils during bacterial pneumonia in mice. Am. J. Respir. Crit. Care Med. 183:1391401

75. Puga I, Cols M, Barra CM, He B, Cassis L, et al. 2012. B cellhelper neutrophils stimulate the diversi-cation and production of immunoglobulin in the marginal zone of the spleen. Nat. Immunol. 13:17080

426 Quinton Mizgerd

Ann

u. R

ev. P

hysio

l. 20

15.7

7:40

7-43

0. D

ownl

oade

d fro

m w

ww

.annu

alre

view

s.org

A

cces

s pro

vide

d by

PER

I - K

E - J

omo

Ken

yatta

Uni

vers

ity o

f Agr

icul

ture

and

Tec

hnol

ogy

on 0

4/25

/15.

For

per

sona

l use

onl

y.


76. Tillett WS, Francis T. 1930. Serological reactions in pneumonia with non-protein somatic fraction ofpneumococcus. J. Exp. Med. 52:56171

77. Gabay C, Kushner I. 1999. Acute-phase proteins and other systemic responses to inammation. N. Engl.J. Med. 340:44854

78. Ahyi AN, Quinton LJ, Jones MR, Ferrari JD, Pepper-Cunningham ZA, et al. 2013. Roles of STAT3 inprotein secretion pathways during the acute-phase response. Infect. Immun. 81:164453

79. Quinton LJ, Blahna MT, Jones MR, Allen E, Ferrari JD, et al. 2012. Hepa

annurev-physiol-021014-071937

Documents

lung infection

tissue resilience

conferimmune resistance

concepts of resistance

disease burdens

annual review of physiology

airspace infection

adaptive immune responses