ABSTRACT
NLRP3 is one of the best characterized innate immune cytosolic sensor. As part of the innate immune response, the NLRP3 inflammasome detects a wide range of danger signals such as pathogens, tissue damages, cellular stress. The priming and activation of NLRP3 lead to the formation of an oligomeric intracellular complex and to the recruitment and activation of caspase-1. Once activated, not only this inflammasome complex controls the processing and release of pro-inflammatory factors including IL-1ß and IL-18, but also the inflammatory cell death pyroptosis mediated by gasdermin D pores. In this review, we describe the role of the NLRP3 inflammasome activation in viral infections with a particular interest on SARS-CoV-2 infection. In addition, we present therapies evaluated or under evaluation targeting the NLRP3 inflammasome pathway as COVID-19 treatment.
Title: L'inflammasome NLRP3 dans la physiopathologie des infections virales - Un focus sur la COVID-19. Abstract: L'inflammasome NLRP3 est un complexe multiprotéique intracellulaire impliqué dans la réponse immunitaire innée. Après la détection de signaux de dangers, tels que ceux provenant d'agents pathogènes, ce complexe s'assemble afin d'initier la production et la sécrétion de molécules pro-inflammatoires, comme l'IL(interleukine)-1ß et l'IL-18. L'inflammasome NLRP3 régule aussi l'activation de la gasdermine D, une protéine impliquée dans la mort cellulaire inflammatoire, ou pyroptose. Cette revue s'intéresse à l'activation et aux rôles de l'inflammasome NLRP3 dans les infections virales et plus particulièrement dans le cas de l'infection par le SARS-CoV-2. Une attention particulière est portée dans cette revue aux traitements évalués, ou en cours d'évaluation, ciblant la voie de l'inflammasome NLRP3 activée au cours de la COVID-19.
Subject(s)
COVID-19 Drug Treatment , COVID-19 , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , COVID-19/immunology , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2ABSTRACT
Dysregulated immune response is the key factor leading to unfavorable coronavirus disease 2019 (COVID-19) outcome. Depending on the pathogen-associated molecular pattern, the NLRP3 inflammasome can play a crucial role during innate immunity activation. To date, studies describing the NLRP3 response during severe acute respiratory syndrome coronavirus 2 infection in patients are lacking. We prospectively monitored caspase-1 activation levels in peripheral myeloid cells from healthy donors and patients with mild to critical COVID-19. The caspase-1 activation potential in response to NLRP3 inflammasome stimulation was opposed between nonclassical monocytes and CD66b+CD16dim granulocytes in severe and critical COVID-19 patients. Unexpectedly, the CD66b+CD16dim granulocytes had decreased nigericin-triggered caspase-1 activation potential associated with an increased percentage of NLRP3 inflammasome impaired immature neutrophils and a loss of eosinophils in the blood. In patients who recovered from COVID-19, nigericin-triggered caspase-1 activation potential in CD66b+CD16dim cells was restored and the proportion of immature neutrophils was similar to control. Here, we reveal that NLRP3 inflammasome activation potential differs among myeloid cells and could be used as a biomarker of a COVID-19 patient's evolution. This assay could be a useful tool to predict patient outcome. This trial was registered at www.clinicaltrials.gov as #NCT04385017.