Severe cases of COVID-19 are characterized by a strong inflammatory process that may ultimately lead to organ failure and patient death. The NLRP3 inflammasome is a molecular platform that promotes inflammation via cleavage and activation of key inflammatory molecules including active caspase-1 (Casp1p20), IL-1β, and IL-18. Although participation of the inflammasome in COVID-19 has been highly speculated, the inflammasome activation and participation in the outcome of the disease are unknown. Here we demonstrate that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and is active in COVID-19 patients. Studying moderate and severe COVID-19 patients, we found active NLRP3 inflammasome in PBMCs and tissues of postmortem patients upon autopsy. Inflammasome-derived products such as Casp1p20 and IL-18 in the sera correlated with the markers of COVID-19 severity, including IL-6 and LDH. Moreover, higher levels of IL-18 and Casp1p20 are associated with disease severity and poor clinical outcome. Our results suggest that inflammasomes participate in the pathophysiology of the disease, indicating that these platforms might be a marker of disease severity and a potential therapeutic target for COVID-19.
These results suggest that suppression of IL-33R expression in neutrophils, preventing IL-33-induced neutrophil migration, may be an important mechanism of anti-TNFalpha therapy of inflammation.
Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to respiratory failure. These patients also develop cytokine storm syndrome, and organ dysfunctions, which is a clinical picture that resembles sepsis. Considering that neutrophil extracellular traps (NETs) have been described as an important factors of tissue damage in sepsis, we investigated whether NETs would be produced in COVID-19 patients and participate in the lung tissue damage. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and respective healthy controls were enrolled. NETs concentration was assessed by MPO-DNA PicoGreen assay or by confocal immunofluorescence. The cytotoxic effect of SARS-CoV-2-induced NETs was analyzed in human epithelial lung cells (A549 cells). The concentration of NETs was augmented in plasma and tracheal aspirate from COVID-19 patients and their neutrophils spontaneously released higher levels of NETs. NETs were also found in the lung tissue specimens from autopsies of COVID-19 patients. Notably, viable SARS-CoV-2 can directly induce in vitro release of NETs by healthy neutrophils in a PAD-4-dependent manner. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represent a potential therapeutic target for COVID-19.
Objective Infiltration of neutrophils into the joints plays an important role in bone erosion and articular destruction in rheumatoid arthritis (RA). Neutrophil trafficking during inflammation is a process that involves activation of chemotactic receptors. Recent findings suggest that changes in chemotactic receptor patterns could occur in neutrophils under certain inflammatory conditions. The aim of this study was to evaluate the gain of responsiveness of neutrophils to CCL2 in RA patients and to assess the role of CCL2 in driving neutrophil infiltration into the joints. Methods Neutrophils were purified from the peripheral blood of patients with RA or from mice with antigen‐induced arthritis (AIA). Expression of CCR2 was evaluated using polymerase chain reaction, flow cytometry, and immunofluorescence analyses. In vitro chemotaxis to CCL2 was assayed to evaluate the functional significance of de novo CCR2 expression. The murine AIA model was used to evaluate the in vivo role of CCR2 in neutrophil infiltration into the joints. Results High CCR2 expression and responsiveness to CCL2 were observed in neutrophils from the blood of patients with early RA and in neutrophils from the blood and bone marrow of mice with AIA. Genetic deficiency or pharmacologic inhibition of CCR2 protected against the infiltration of neutrophils into the joints. This protection was not associated with an impairment of the neutrophil chemotactic ability or CXC chemokine production in the joints. Moreover, adoptive transfer of wild‐type mouse neutrophils to CCR2‐deficient mice restored neutrophil infiltration and the articular mechanical hyperalgesia associated with joint inflammation. Conclusion These findings suggest that CCR2 is directly involved in the detrimental infiltration of neutrophils into the joints in patients with RA, showing a new inflammatory role of CCR2 during RA flares or active disease.
RESUMOA dengue é uma arbovirose transmitida principalmente pela picada do mosquito Aedes aegypti. Pode ser assintomática ou apresentar amplo espectro clínico, variando de doença febril autolimitada até formas graves, que podem evoluir com choque circulatório e óbito. Para evitar esse desfecho, a precocidade no diagnóstico da doença e na detecção de sinais de alarme, que indicam evolução desfavorá-vel; assim como a instituição de tratamento adequado, são fundamentais. Não há tratamento específi-co, ele é apenas sintomático e de suporte. Até o momento, não existe vacina disponível para prevenção da doença, sendo o controle do vetor a medida mais efetiva. Palavras-chave: Introdução Introdução Introdução Introdução IntroduçãoNos últimos anos, a dengue se tornou um problema de saúde pública. Isso devido ao grande núme-ro de casos da doença, fazendo dela a mais frequente das arboviroses que acomete o ser humano. A morbidade ocasionada, já que a intensa mialgia e prostração podem levar o doente ao afastamento das suas atividades produtivas por dias, associado a sua mortalidade, podem ser elevadas dependendo da forma da doença e da precocidade e eficácia do tratamento médico instituído. 1 É transmitida principalmente por meio da picada do mosquito Aedes aegypti, apesar de haver outra espécie, o Aedes albopictus, que possui morfologia e capacidade proliferativa semelhantes ao anterior e também é responsável por alguns surtos da doença em países do continente asiático.2 No Brasil, o Aedes albopictus foi introduzido aproximadamente em 1980, mas até o momento não foi identificado nenhum exemplar infectado pelo vírus da dengue. O Aedes aegypti é um mosquito de hábito diurno, principalmente no início da manhã e no final da tarde; tem preferência por ambientes urbanos e intradomiciliares; e alimenta-se principalmente de sangue humano. 3A proliferação do mosquito é feita pela postura de ovos pela fêmea em coleções de água parada onde posteriormente eles eclodem originando as larvas. O tempo decorrido entre a eclosão do ovo e o mosquito adulto é cerca de 10 dias, sendo influenciado por fatores como a temperatura, que acelera esse processo. O ovo do mosquito sobrevive por até um ano fora da água, aguardando condições ambientais favoráveis para se desenvolver. 3 T T T T Tr r rr ransmissão e pa ansmissão e pa ansmissão e pa ansmissão e pa ansmissão e pato to to to togênese gênese gênese gênese gênese O mosquito adquire o vírus ao se alimentar do sangue de doente que se encontra na fase de viremia, que começa um dia antes do surgimento da febre e vai até o sexto dia de doença. O vírus vai se localizar nas glândulas salivares do mosquito, onde se prolifera e aí permanece, deixando o artrópode infectante durante toda a sua vida.5 Uma vez infectada a fêmea do mosquito inocula o vírus junto com a sua saliva ao picar a pessoa sadia. Além disso, a fêmea também faz a transmissão transovariana do vírus para a sua prole, favorecendo a expansão da doença. A Dengue Clássica ou Febre da dengue se caracteriza por febre alta de início súbito (pr...
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