SARS-CoV-2 triggers inflammasome-dependent release of pro-inflammatory cytokine IL-1β and pyroptosis, therefore, contributes to the huge inflammatory response observed in severe COVID-19 patients. Less is known about the engagement of inflammasome in neutrophils, main players in tissue injury and severe infection. We studied the activation of the inflammasome in neutrophils from severe COVID-19 patients and assessed its consequence in term of cells contribution to disease pathogenesis. We demonstrated that NLRP3 inflammasome is dramatically activated in neutrophils from severe COVID-19 patients and that the specific inhibition of NLRP3 reverts neutrophils' activation. Next, the stimulation of severe patients' neutrophils with common NLRP3 stimuli was not able to further activate the inflammasome, possibly due to exhaustion or increased percentage of circulating immature neutrophils. Collectively, our results demonstrate that the NLRP3 inflammasome is hyperactivated in severe COVID-19 neutrophils and its exhaustion may be responsible for the increased susceptibility to subsequent (and possibly lethal) infections. Our findings thus include a novel piece in the complex puzzle of COVID-19 pathogenesis.

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TMEM176B was recently described as a negative modulator of Nlrp3 in ammasome activation in mice. In the mouse model, the inhibition of TMEM176B leads to an increased anti-tumoral activity which is dependent on Nlrp3. Since we have recently shown that single nucleotide variants (SNPs) in in ammasome genes, including NLRP3, signi cantly affect colorectal cancer (CRC) prognosis, we proposed to investigate here the association between genetic variants in TMEM176B and CRC prognosis. MethodsConsidering that, up to now, no genetic study analyzing this gene in humans exists, we selected possible functional SNPs and genotyped them in a cohort of CRC patients submitted to surgery and followed up for more than 10 years. Genotype-guided assays were realized to evaluate the effect of the variant on NLRP3 in ammasome activation. Gene expression from The Cancer Genome Atlas (TCGA) cohort were analyzed to valid possible prognostic and predictive features. ResultsWe identi ed the Ala134Thr variant (rs2072443) in TMEM176B as a protective factor for CRC prognosis. This SNP is associated with decreased gene expression and with an increased activation of NLRP3 in ammasome, at least in monocytes and dendritic cells. Furthermore, low TMEM176B expression is associated with higher overall survival. ConclusionAltogether these ndings supported the role of TMEM176B in NLRP3 in ammasome biology and for the rst time demonstrated the genetic association between rs2072443 and CRC in humans.

Objective and design The heterogeneity of response to SARS-CoV-2 infection is directly linked to the individual genetic background. Genetic variants of inflammasome-related genes have been pointed as risk factors for several inflammatory sterile and infectious disease. In the group of inflammasome receptors, NLRP1 stands out as a good novel candidate as severity factor for COVID-19 disease. Methods To address this question, we performed an association study of NLRP1 , DPP9 , CARD8 , IL1B , and IL18 single nucleotide variants (SNVs) in a cohort of 945 COVID-19 patients. Results The NLRP1 p.Leu155His in the linker region, target of viral protease, was significantly associated to COVID-19 severity, which could contribute to the excessive cytokine release reported in severe cases. Conclusion Inflammasome genetic background contributes to individual response to SARS-CoV-2. Supplementary Information The online version contains supplementary material available at 10.1007/s00011-022-01670-3.