INSIGHTS

COVID-19 stokes inflammasomesClare Bryant

The poor success rate of treating patients with aggressive sepsis in SARS-CoV-2 infections has highlighted again thechallenges of managing systemic inflammatory conditions. In this issue of JEM, Rodrigues et al. (https://doi.org/10.1084/jem.20201707) discuss the role of inflammasome activation in COVID-19 disease severity, opening new possibilities fortherapeutic management of sepsis syndromes.

In this issue of JEM, Rodrigues et al. (2020)show that activation of inflammasomes bySARS-CoV-2 infection is linkedwith COVID-19 disease severity in patients, potentiallyproviding new therapeutic avenues for thisintractable condition. Inflammasomes aremacromolecular inflammatory signalingcomplexes that may be canonical (composedof a receptor, such as a nucleotide oligo-merization domain leucine rich repeat re-ceptor [NLR] or AIM-2 like receptor; anadaptor [ASC]; and an effector [caspase 1])or noncanonical (composed of caspase 4 or 5in humans or caspase 11 in mice; Broz andDixit, 2016). Activation of canonical in-flammasomes results in the processing ofpro–IL-1β and pro-IL-18 to their bioactiveforms along with cleavage of the celldeath–inducing protein gasdermin D to re-lease its pore-forming N-terminal (Shi et al.,2017). The NLRP3 inflammasome is trig-gered by a diverse array of stimuli, many ofwhich would be released in response to thekind of cell damage that occurs duringsepsis (Swanson et al., 2019). It is linked tomany diseases including type II diabetes,Alzheimer’s disease, and Parkinson’s dis-ease, with NLRP3 inhibitors currently be-ing tested for a range of conditions in theclinic (Swanson et al., 2019). Noncanonicalinflammasome activity induces gasderminD–driven pyroptotic cell death, but alsoindirectly activates the NLRP3 inflammasomeand is important in sepsis models (Broz andDixit, 2016).

The challenges of treating the severesystemic inflammatory syndrome associatedwith COVID-19 in patients (Wang et al.,2020) have highlighted, yet again, the im-portance of sepsis and our very limited ca-pacity for therapeutic intervention in thiscondition. Despite sepsis being a hugelyimportant unmet medical need and the re-cent explosion of knowledge in inflamma-tory mechanistic biology, little progress hasbeen made in new treatments for it. Anumber of studies, particularly those in ro-dents, have suggested that activation of theNLRP3 inflammasome is important in dif-ferent sepsis models (Danielski et al., 2020),and there has been much speculation thatNLRP3 would be linked to the pathogenesisof COVID-19. The Zamboni paper (Rodrigueset al., 2020) provides nice evidence to sup-port this hypothesis (see figure) in SARS-CoV-2–infected patients; however, it alsosuggests a role for other inflammasomes inthe pathogenesis of this disease. This sug-gests that inhibition of NLRP3 alone mayhave limited usefulness in COVID-19 sepsis,although its importance in other humanseptic syndromes remains to be deter-mined. The involvement of more than oneinflammasome in COVID-19 sepsis suggestsapproaches that inhibitmultiple inflammasomesand/or a common effector mechanismmayprove a useful adjunct to current therapeuticapproaches.

Strategies for therapeutic targeting ofthe IL-1β and IL-18 cytokines processed by

inflammasomes are in the clinic and/or inlate phase clinical trials (Mantovani et al.,2019; Mokry et al., 2019). Patients with au-toinflammatory syndromes driven by gainof function mutations in NLRP3 respondwell to treatments that neutralize IL-1βsuch as the IL-1 receptor antagonist ana-kinra or the neutralizing monoclonal anti–IL-1β antibody canakinumab (Mantovaniet al., 2019). In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study(CANTOS), neutralization of IL-1β had ben-eficial effects in preventing atherosclerosis-associated cardiovascular events, arthritis,gout, and reduced lung cancer incidence,but an important side effect of the treat-ment was an increased infection suscepti-bility in patients (Mantovani et al., 2019).Even though there are elevated levels of IL-1β in sepsis, inhibition of the effects of this

Insights from Clare Bryant.

.............................................................................................................................................................................Departments of Medicine and Veterinary Medicine, The University of Cambridge, Cambridge, UK.

Clare Bryant: Ceb27@cam.ac.uk.

© 2020 Bryant. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after thepublication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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cytokine has yet to show beneficial effects inclinical trials for severe systemic inflamma-tory syndromes; although this is being testedin COVID-19 patients, any therapy whichincreases the susceptibility of patients to in-fection may well be problematic. IL-18 levelsin sepsis are linked to disease severity andpatient prognosis, but whether inhibition ofthis cytokine alone would be beneficial inseptic patients has yet to be determined (Zhuet al., 2020). Inhibition of both IL-1β and IL-18 is effective at reducing sepsis in rodentmodels (Vanden Berghe et al., 2014), but thiscombination approach of neutralizing more

than one cytokine has yet to be exploredextensively in patients because of the po-tential infection risks.

Inhibition of caspase activity, particularlycaspase 1, 8, and 4/5/11, could simultaneouslytarget many inflammasomes (Chauhan et al.,2020).Multiple caspase-driven cell deathpathways are likely to be important insepsis, including apoptosis, necroptosis,and pyroptosis. There is considerable crosstalk between caspase-dependent cell deathpathways (Kesavardhana et al., 2020) andredundancy either in cytokine-processingmechanisms or in cytokine-signaling pathways.

Small molecule and peptide inhibitors ofcaspases have been developed, and in animalsepsis models these inhibitors can be pro-tective with or without accompanying cy-tokine blockade (Aziz et al., 2014). Thecomplexities of caspase activity in inflam-mation and infection, particularly with thediverse genetic background of the humanpopulation, along with toxicity issues associ-ated with these inhibitors means these drugs,have not made it to the clinic for treatingsepsis (Aziz et al., 2014). Inhibition of gas-dermin D activity as the common executionerprotein for all inflammasomes could alsoprovide a new avenue for treating sepsisassociated with inflammasome activation(Orning et al., 2019). The repurposing of ex-isting drugs, as well as the development ofnew molecules, to inhibit gasdermin D ac-tivity and hence block inflammation are thesubject of intensive research at the moment(Lieberman et al., 2019).

Therapeutic strategies in sepsis requiretargeting the overactive cytokine responsewith immunomodulators while maintain-ing a sufficient inflammatory response forpathogen clearance. There is, unfortunately,a sad history of unsuccessful clinical trials insepsis, including the failure of many cyto-kine neutralization strategies and inhibitorsof Toll-like receptor 4. The reasons for thisare many, including the multifactorialcauses of sepsis (bacterial, viral, trauma),the complex network of interlinked inducedimmune responses, how these responseschange during the course of systemic in-flammation, the genetic background of thepatient, and the point at which new inter-ventions are tested, particularly toward theend of a life course. Application of machinelearning to the analysis of the large datasetsgenerated from different cohorts of septicpatients (Giannini et al., 2019), for example,from those with COVID-19, should help tostratify different patient groups to select themost appropriate therapeutic strategies.Rodrigues et al. (2020) have linked in-flammasome activity with COVID-19 diseaseseverity, which potentially provides an im-portant biomarker to assist in patient strati-fication. Taking out a single cytokine orsignaling pathway is unlikely to be successfulin treating sepsis because of functional re-dundancies and the potential for destabilizingthe various immunological balances particu-larly between inflammation, immunosup-pression, and anti-inflammatory pathways.

NLRP3 inflammasome activation in pulmonary tissue of COVID-19 patients. (A and B) Representativelung histological of controls (CT; A) or COVID-19 patients (P; B) stained with anti–SARS-CoV-2 antibody.(C and D) Multiplex immunohistochemistry staining with anti–SARS-CoV-2, anti-CD14, and anti-NLRP3antibodies. (E and F) Quantification of NLRP3 (E) or ASC puncta (F) in pulmonary tissues of controls andCOVID-19 patients. (G and H) Multiphoton microscopy of pulmonary tissues stained with anti-NLRP3 (G)or anti-ASC (H) antibodies showing inflammasome puncta. Please refer to Fig. 3 in the related article byRodrigues et al. (2020) for a full explanation of the figure.

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Inflammasome activation, particularly in thecontext of NLRP3, acts as a regulator of im-mune homeostasis, so whether inhibition ofthis pathway will prove a useful therapeuticapproach in sepsis, particularly as part ofcombination therapy, remains to be seen.

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