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. 2023 Sep 5;119(11):2046-2060.
doi: 10.1093/cvr/cvad084.

NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis

Nicola Potere  1 , Evan Garrad  2   3 , Yogendra Kanthi  2 , Marcello Di Nisio  1 , Gilles Kaplanski  4   5 , Aldo Bonaventura  6 , Jean Marie Connors  7 , Raffaele De Caterina  8   9   10 , Antonio Abbate  11
Affiliations

NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis

Nicola Potere et al. Cardiovasc Res. .

Abstract

Immunothrombosis-immune-mediated activation of coagulation-is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as in severe coronavirus disease 2019 (COVID-19). The NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines of the interleukin (IL)-1 family, IL-1β and IL-18, and induces pyroptotic cell death. Activation of the NLRP3 inflammasome pathway also promotes immunothrombotic programs including release of neutrophil extracellular traps and tissue factor by leukocytes, and prothrombotic responses by platelets and the vascular endothelium. NLRP3 inflammasome activation occurs in patients with COVID-19 pneumonia. In preclinical models, NLRP3 inflammasome pathway blockade restrains COVID-19-like hyperinflammation and pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety and efficacy and is approved for the treatment of hypoxaemic COVID-19 patients with early signs of hyperinflammation. The non-selective NLRP3 inhibitor colchicine reduced hospitalization and death in a subgroup of COVID-19 outpatients but is not approved for the treatment of COVID-19. Additional COVID-19 trials testing NLRP3 inflammasome pathway blockers are inconclusive or ongoing. We herein outline the contribution of immunothrombosis to COVID-19-associated coagulopathy, and review preclinical and clinical evidence suggesting an engagement of the NLRP3 inflammasome pathway in the immunothrombotic pathogenesis of COVID-19. We also summarize current efforts to target the NLRP3 inflammasome pathway in COVID-19, and discuss challenges, unmet gaps, and the therapeutic potential that inflammasome-targeted strategies may provide for inflammation-driven thrombotic disorders including COVID-19.

Keywords: COVID-19; Coagulation; Endotheliopathy; Interleukin-1; NLRP3 inflammasome; Pyroptosis; Thrombosis.

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Conflict of interest statement

Conflict of interest: N.P. has received a training fellowship from the International Society on Thrombosis and Haemostasis and research funding from the International Network of VENous Thromboembolism Clinical Research Networks (INVENT), outside of the present work. Y.K. is an inventor on a patent application (US20180369278A1) by the University of Michigan on the use of biogases in vascular disease. M.D.N. reports personal fees as an invited speaker from Bayer, Daiichi Sankyo, and Viatris, personal fees for advisory board membership from LEO Pharma and Pfizer, and institutional funding from LEO Pharma. G.K. has received honorary fees from Swedish Orphan Biovitrum, Chugai-Roche, and Amgen. A.B. received a travel grant from Kiniksa Pharmaceuticals Ltd to attend the 2019 AHA Scientific Sessions and honoraria from Effetti s.r.l. (Milan, Italy) to collaborate on the medical website http://www.inflammology.org, outside the present work. J.M.C. has received personal fees for scientific advisory boards and consulting from Abbott, Anthos, Alnylam, Bristol Myers Squibb, Five Prime Therapeutics, Pfizer, Takeda, and research funding from CSL Behring, outside of the submitted work. R.D.C. has received personal fees from Boehringer-Ingelheim, Bayer, BMS-Pfizer, Daiichi Sankyo, Novartis, Roche, Sanofi, Amgen, Milestone, Menarini, AstraZeneca, and Guidotti, outside the submitted work. A.A. has received research grant funding and has served as a paid scientific advisor to Implicit Biosciences, Kiniksa, Lilly, Merck, Novartis, Novo Nordisk, Olatec, R-Pharm, Serpin Pharma, and Swedish Orphan Biovitrum, outside of the submitted work. E.G. has nothing to disclose.

Figures

Figure 1
Figure 1
Overview of the pathogenetic mechanisms implicated in COVID-19-associated coagulopathy. Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin Type 1 motifs, member 13; ACE2, angiotensin-converting enzyme 2; AMI, acute myocardial infarction; AT, antithrombin; DVT, deep vein thrombosis; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; PE, pulmonary embolism; ROS, reactive oxygen species; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TM, thrombomodulin; TNF, tumour necrosis factor; VCAM-1, vascular cell adhesion molecule 1; VWF, von Willebrand factor. Figure created with BioRender.com.
Figure 2
Figure 2
NLRP3 inflammasome pathway activation in COVID-19-associated hyperinflammation and lung immunopathology. Abbreviations: ACE2, angiotensin-converting enzyme 2; ARDS, acute respiratory distress syndrome; Casp-1, caspase-1; DAMPs, damage-associated molecular patterns; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; eATP, extracellular ATP; PAMPs, pathogen-associated molecular-patterns; ROS, reactive oxygen species; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Figure created with BioRender.com.
Figure 3
Figure 3
Proposed role of NLRP3 inflammasome pathway activation in COVID-19-associated coagulopathy and immunothrombosis. Abbreviations: AT, antithrombin; FXIIa, factor XIIa; CathG, cathepsin G; GSDMD, gasdermin D; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; IL-1R, interleukin-1 receptor; MPO, myeloperoxidase; NE, neutrophil elastase; NET, neutrophil extracellular trap; P-sel, P-selectin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; VWF, von Willebrand factor. Figure created with BioRender.com.
Figure 4
Figure 4
Pharmacological agents addressing COVID-19-associated inflammation and thrombosis. Abbreviations: FXa, factor Xa; IL, interleukin; IL-1R, interleukin-1 receptor; IL-6R, interleukin-6 receptor; IL-1Ra, interleukin-1 receptor antagonist; JAK, Janus kinase; NF-κB, nuclear factor-kappa B; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STAT, signal transducer and activator of transcription protein. Figure created with BioRender.com.
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