Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment - 04/10/22

Doi : 10.1016/j.jaci.2022.05.029

Arinna Bertoni, PhD ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Federica Penco, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Hilaria Mollica, PhD ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Paola Bocca, BS ^a, Ignazia Prigione, PhD ^a, Anna Corcione, PhD ^a, Davide Cangelosi, PhD ^c, Francesca Schena, PhD ^a, Genny Del Zotto, PhD ^d, Adriana Amaro, PhD ^e, Noemi Paladino, BS ^a, Emanuele Pontali, MD ^f, Marcello Feasi, MD ^f, Sara Signa, MD ^a,^b, Marta Bustaffa, MD ^a, Roberta Caorsi, MD ^a, Serena Palmeri, MD ^b, Paola Contini, PhD ^g, Raffaele De Palma, MD, PhD ^g, Ulrich Pfeffer, PhD ^e, Paolo Uva, PhD ^c,^h, Anna Rubartelli, MD ⁱ, Marco Gattorno, MD ^a,^⁎,^{^{‡
These authors contributed equally to this work.}} , Stefano Volpi, MD, PhD ^a,^b,^⁎,^{^{‡
These authors contributed equally to this work.}}
^a UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy
^b DINOGMI, Università degli Studi di Genova, Genova, Italy
^c Clinical Bioinformatics Unit and Diagnostics, IRCCS Istituto Giannina Gaslini, Genova, Italy
^d Department of Research and Diagnostics, IRCCS Istituto Giannina Gaslini, Genova, Italy
^e IRCCS Ospedale Policlinico San Martino, Genova, Italy
^f Ente Ospedaliero Ospedale Galliera, Genova, Italy
^g Department of Internal Medicine, University of Genoa and IRCCS IST-Ospedale San Martino, Genova, Italy
^h Italian Institute of Technology, Genova, Italy
ⁱ Istituto Giannina Gaslini, Genova, Italy

^∗Corresponding author: Marco Gattorno, MD, or Stefano Volpi, MD, PhD, UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy.UOSD Centro per le Malattie Autoinfiammatorie e ImmunodeficienzeIRCCS Istituto Giannina GasliniVia G. Gaslini 5Genova16147Italy

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Abstract

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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Graphical abstract

El texto completo de este artículo está disponible en PDF.

Key words : NLRP3 inflammasome, IL-1β, inflammation, SARS-CoV-2

Abbreviations used : ASC, COVID-19, GSEA, MAS, NES, NLRP3, ORF3a, SARS-CoV-2

Esquema

Methods

Study design and participants

Patient and public involvement

Isolation and stimulation of cells

Secretion of cytokines

RNA and real-time PCR

DNA transfection

Imaging

Detection of ASC speck by fluorescence-activated cell sorting

FLICA-Caspase-1 staining

RNA-sequencing data processing

Bioinformatic analysis for RNA sequencing

Statistical analysis

Results

Discussion

	S.V. received financial support from AMRI (Associazione Malattie Reumatiche Infantili).
	Disclosure of potential conflict of interest: M. Gattorno reports consultancies and speaker’s fee from Novartis and SOBI. S. Volpi, A. Bertoni, F. Penco, P. Bocca, I. Prigione, A. Corcione, and F. Schena report speaker fee from SOBI. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 150 - N° 4

P. 796-805 - octobre 2022 Regresar al número

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Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment - 04/10/22

Abstract

Background

Objectives

Methods

Results

Conclusions

Graphical abstract

Esquema

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