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Inflammasome Activation at the Crux of Severe COVID-19

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Inflammasome Activation at the Crux of Severe COVID-19 PROGRESS based on RNA sequencing, often of thawed cells, and infected, activated or dying cells do Inflammasome activation at the crux not survive freeze–thaw well, which could skew results. Moreover, inflammasome of severe COVID-19 activation does not directly induce tran- scriptional responses, and its detection is less straightforward than that of most other Setu M. Vora, Judy Lieberman and Hao Wu signalling pathways. Nonetheless, several Abstract | The COVID-19 pandemic, caused by severe acute respiratory syndrome studies are now accumulating that support coronavirus 2 (SARS- CoV-2), results in life- threatening disease in a minority of direct (infection-induced) and indirect inflammasome activation and the critical patients, especially elderly people and those with co- morbidities such as obesity role of inflammasomes in severe COVID-19. and diabetes. Severe disease is characterized by dysregulated cytokine release, Here we discuss the available evidence, pneumonia and acute lung injury, which can rapidly progress to acute respiratory potential mechanisms and the implications distress syndrome, disseminated intravascular coagulation, multisystem failure and for therapy. death. However, a mechanistic understanding of COVID-19 progression remains Inflammasomes unclear. Here we review evidence that SARS-CoV-2 directly or indirectly activates Key to inflammation and innate immunity, inflammasomes, which are large multiprotein assemblies that are broadly inflammasomes are large, micrometre- responsive to pathogen- associated and stress- associated cellular insults, leading scale multiprotein cytosolic complexes to secretion of the pleiotropic IL-1 family cytokines (IL-1β and IL-18), and that assemble in response to pathogen- pyroptosis, an inflammatory form of cell death. We further discuss potential associated molecular patterns (PAMPs) mechanisms of inflammasome activation and clinical efforts currently under way or damage-associated molecular patterns (DAMPs) and trigger proinflammatory to suppress inflammation to prevent or ameliorate severe COVID-19. cytokine release as well as pyroptosis, a proinflammatory lytic cell death30,31 (Fig. 1). Severe acute respiratory syndrome while global vaccination efforts strive to Upon activation by PAMPs or DAMPs, coronavirus 2 (SARS-CoV-2), the virus meet the challenge of ending the pandemic, canonical inflammasome sensors — mainly responsible for COVID-19, has so far the appearance of immune-evasive viral in monocytes, macrophages and barrier infected more than 190 million people variants and the unlikelihood of reaching epithelial cells — oligomerize and recruit and caused death of more than 4.1 million immediate herd immunity underscore the the adaptor apoptosis-associated speck-like people worldwide. The virus primarily continued need for additional treatments protein containing a CARD (ASC) to infects the respiratory tract, causing mitigating disease progression15–19. form inflammasome specks, within which fever, sore throat, anosmia and dyspnoea, Most researchers agree that an inappro- the inflammatory caspase 1 is recruited but its tissue tropism still remains to be priate hyperinflammatory response and activated. Inflammasome sensors are fully understood. As many as 10–15% lies at the root of many severe cases of activated in response to different triggers of patients develop severe pneumonia, COVID-19, driven by overexuberant and differ in their overall specificities with some cases progressing to hypoxia inflammatory cytokine release. Consistently, to PAMPs or DAMPs. NLRP3, the most and acute respiratory distress syndrome co-morbidities, such as obesity, diabetes, broadly activated inflammasome sensor (ARDS), which requires mechanical heart disease, hypertension and ageing, and a member of the nucleotide-binding ventilation in a critical care setting and has which are prognostic of poor outcome, domain- and leucine-rich repeat- containing high mortality. Patients can also develop are associated with high basal inflam- protein (NLR) family, responds to an array multi- organ failure, acute kidney injury and mation7,11,20,21. It has been proposed since of insults to the cell that cause cytosolic disseminated intravascular coagulation, the beginning of the pandemic that these K+ efflux, Ca2+ cytosolic influx or release among a host of other disorders1–11. Aside co- morbidities and the ensuing hyper- of mitochondrial reactive oxygen species from supportive care, only a few treatments inflammatory response may be aetiologically (ROS)31,32. These insults include extracel- have been approved for COVID-19, and linked through overactive inflammasome lular ATP, membrane permeabilization by their reduction of mortality has been signalling, which may account for the asso- pore- forming toxins and large extracellular limited12–14. Although several vaccines ciation of these co- morbidities with severe aggregates such as uric acid crystals, choles- against SARS- CoV-2 have been approved COVID-19 in the context of chronic inflam- terol crystals and amyloids30. Other sensors, and are being administered internationally, mation as well as for COVID-19 progression such as AIM2 and NLRC4, are tuned to there will still be a significant number of in the context of a robust acute inflamma- recognize specific PAMPs and DAMPs, infections owing to people who are not tory response to infection22–29. However, such as cytosolic double-stranded DNA vaccinated in regions with inadequate access many of the studies that seek to understand and bacterial proteins, respectively31. In a or acceptance of vaccination. In addition, the immune response to SARS-CoV-2 are parallel pathway, the mouse inflammatory NATURE REVIEWS | IMMUNOLOGY 0123456789();: PROGRESS Anti-spike antibody SARS-CoV-2 Virus-intrinsic inflammasome activation Host-intrinsic inflammasome activation K+ ACE2 FcγR ORF3a ↓ K+ NLRP3 inflammasome Caspase 1 N Pro-IL-1β, GSDMD (FL) pro-IL-18 ERGIC Ca2+ GSDMD (CT) E Mitochondrial damage Golgi apparatus IL-1β, GSDMD (NT) IL-18 AIM2 inflammasome Caspase 4/ ROS dsDNA caspase 5 + Tissue ↓ K GSDMD factor pore P2X7 oxPLs C5a K+ ROS ATP Tissue Dead cells Bacterial Lung surfactant factor- IL-6, IL-8, co-infection positive TNF, CRP, LDH EVs D-dimer Fig. 1 | Virus-intrinsic and host-intrinsic mechanisms of inflammasome and NLRP3 activation. Dead cells, bacterial co-infection or damaged mito- activation. Virus intrinsic mechanisms (red arrows): severe acute respira- chondria can result in cytosolic double- stranded DNA (dsDNA), which tory syndrome coronavirus 2 (SARS-CoV-2) virions enter epithelial cells via activates the AIM2 inflammasome. NLRP3 and AIM2 inflammasome assem- angiotensin- converting enzyme 2 (ACE2) and can enter monocytes by bly activates caspase 1, which cleaves full- length (FL) gasdermin D binding to anti- spike antibodies followed by Fc receptor for IgG (FcγR)- (GSDMD) into amino- terminal (NT) and carboxy- terminal (CT) fragments. mediated internalization. Upon translation of the viral genome, the viro- The GSDMD NT fragment binds to the plasma membrane, oligomerizes porins ORF3a and E can trigger K+ efflux or Ca2+ influx to promote NLRP3 and inserts itself as a pore. Caspase 1 also cleaves pro-IL-1 β and pro- IL-18 activation. Viral N protein can bind directly to NLRP3, resulting in its acti- into their mature forms, which are released through the GSDMD pore. vation. Host- intrinsic mechanisms (blue arrows): oxidation of lung sur- IL-1β can activate macrophages to secrete additional proinflammatory factant phospholipids results in oxidized phospholipids (oxPLs), which cytokines such as IL-6. Pyroptosis results after further membrane damage, can activate caspase 4 and/or caspase 5 to promote noncanonical which releases lactate dehydrogenase (LDH) and is associated with inflam masome activation. Complement products such as C5a can activate the formation of tissue factor- enriched extracellular vesicles (EVs). CRP, NLRP3 by promoting accumulation of reactive oxygen species (ROS). C-reactive protein; ERGIC, endoplasmic reticulum–Golgi intermediate ATP released by dead cells binds to P2X7 receptor, which causes K+ efflux compartment; TNF, tumour necrosis factor. caspase 11 and human caspase 4 and Upon activation, caspase 1 processes itself into cell and organelle membranes to caspase 5 sense PAMPs and DAMPs such as pro-IL-1β and pro-Ι L-18 into their functional form sizable pores37–41. These pores are large bacterial lipopolysaccharide (LPS) that gain cytokine forms, and all inflammatory caspases enough to directly release IL-1β and ΙL-18, cytosolic access and endogenous oxidized cleave the pyroptotic executor protein strong pleiotropic inducers of downstream phospholipids, leading directly to mem- gasdermin D (GSDMD) into amino-terminal immune responses, as well as various brane damage or pyroptosis, and secondary and carboxy- terminal fragments. The alarmins, such as ATP and high mobility K+ efflux followed by noncanonical NLRP3 GSDMD amino- terminal fragment binds group protein B1 (HMGB1). Pyroptosis inflammasome activation33–36. to acidic lipids, oligomerizes and inserts occurs when the plasma membrane is www.nature.com/nri 0123456789();: PROGRESS compromised, resulting in the release of CXC- chemokine ligand 8 (CXCL8; also lavage fluid (BALF) — a readout more larger alarmins such as lactate dehydrogenase known as IL-8) and proinflammatory reflective of the lung microenvironment (LDH) tetramer (144 kDa), which is a cytokines such as IL-6 and tumour necrosis with massive monocyte, macrophage
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