Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically il...

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Published in:Journal of allergy and clinical immunology 2022-10, Vol.150 (4), p.796-805
Main Authors: Bertoni, Arinna, Penco, Federica, Mollica, Hilaria, Bocca, Paola, Prigione, Ignazia, Corcione, Anna, Cangelosi, Davide, Schena, Francesca, Del Zotto, Genny, Amaro, Adriana, Paladino, Noemi, Pontali, Emanuele, Feasi, Marcello, Signa, Sara, Bustaffa, Marta, Caorsi, Roberta, Palmeri, Serena, Contini, Paola, De Palma, Raffaele, Pfeffer, Ulrich, Uva, Paolo, Rubartelli, Anna, Gattorno, Marco, Volpi, Stefano
Format: Article
Language:English
Subjects:
Anti-Inflammatory Agents
COVID-19 Drug Treatment
Cytokine Release Syndrome - drug therapy
Cytokines - metabolism
DNA, Complementary
Humans
IL-1β
Inflammasomes - metabolism
inflammation
Interleukin 1 Receptor Antagonist Protein - therapeutic use
Interleukin-1beta - metabolism
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
NLR Proteins
NLRP3 inflammasome
Receptors, Interleukin-1
SARS-CoV-2
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Summary:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients; however, the mechanisms by which SARS-CoV-2 triggers such an extensive inflammation remain unexplained. To dissect the mechanisms underlying SARS-CoV-2–associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1β, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes. We analyzed nod-like receptor protein 3 pathway activation by means of confocal microscopy, plasma cytokine measurement, cytokine secretion following in vitro stimulation of blood circulating monocytes, and whole-blood RNA sequencing. The role of open reading frame 3a SARS-CoV-2 protein was assessed by confocal microscopy analysis following nucleofection of a monocytic cell line. We found that circulating monocytes from patients with COVID-19 display ASC (adaptor molecule apoptotic speck like protein–containing a CARD) specks that colocalize with nod-like receptor protein 3 inflammasome and spontaneously secrete IL-1β in vitro. This spontaneous activation reverts following patient’s treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV-2 protein resulted in ASC speck formation. These results provide further evidence that IL-1β targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19. [Display omitted]
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2022.05.029