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

BACKGROUND: 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 c...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Academy of Allergy, Asthma & Immunology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272569/
https://www.ncbi.nlm.nih.gov/pubmed/35835255
http://dx.doi.org/10.1016/j.jaci.2022.05.029
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author 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
author_facet 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
author_sort Bertoni, Arinna
collection PubMed
description BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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spelling pubmed-92725692022-07-11 Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment 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 J Allergy Clin Immunol Covid-19 BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. American Academy of Allergy, Asthma & Immunology 2022-10 2022-07-11 /pmc/articles/PMC9272569/ /pubmed/35835255 http://dx.doi.org/10.1016/j.jaci.2022.05.029 Text en © 2022 American Academy of Allergy, Asthma & Immunology. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Covid-19
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
Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment
title Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment
title_full Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment
title_fullStr Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment
title_full_unstemmed Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment
title_short Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment
title_sort spontaneous nlrp3 inflammasome-driven il-1-β secretion is induced in severe covid-19 patients and responds to anakinra treatment
topic Covid-19
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272569/
https://www.ncbi.nlm.nih.gov/pubmed/35835255
http://dx.doi.org/10.1016/j.jaci.2022.05.029
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