RESUMO
The aim of this study is to investigate the inflammasome dysregulation in peripheral blood leukocytes of VEXAS patients. The constitutive and in vitro triggered activation of inflammasome in PBMC and neutrophils was analyzed in two Brazilian patients with typical UBA1 mutations, and compared with healthy donors. Our findings highlight the constitutive activation of caspase-1 in VEXAS leukocytes, accompanied by increased plasma levels of IL-18. Furthermore, upon stimulation of isolated peripheral blood mononuclear cells (PBMC) and neutrophils, we observed not only the exhaustion of NLRP3 and NLRP1/CARD8 pathways in VEXAS PBMC but also a significant increase in NLRP3-mediated NETs release in VEXAS neutrophils. These findings support previous studies on the contribution of the inflammasome to VEXAS pathogenesis, identifying at least two profoundly affected pathways (NLRP3 and NLRP1/CARD8) in VEXAS peripheral blood.
Assuntos
Proteínas Adaptadoras de Sinalização CARD , Inflamassomos , Interleucina-18 , Leucócitos Mononucleares , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas NLR , Neutrófilos , Humanos , Inflamassomos/metabolismo , Inflamassomos/imunologia , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-18/sangue , Interleucina-18/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Proteínas NLR/genética , Feminino , Masculino , Neutrófilos/imunologia , Caspase 1/genética , Idoso , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Enzimas Ativadoras de Ubiquitina/genética , Febre/imunologia , Mutação , Brasil , Proteínas de NeoplasiasRESUMO
SARS-CoV-2 triggers inflammasome-dependent release of pro-inflammatory cytokine IL-1ß 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.