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...

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a hyperinflammatory state and lymphocytopenia, a hallmark that appears as both signature and prognosis of disease severity outcome. Although cytokine storm and sustained inflammatory state are commonly associated with immune cell depletion, it is still unclear whether direct SARS-CoV-2 infection of immune cells could also play a role in this scenario by harboring virus replication. We found that monocytes, as well as both B and T lymphocytes, were susceptible to SARS-CoV-2 infection in vitro, accumulating double-stranded RNA consistent with viral RNA replication and ultimately leading to expressive T cell apoptosis. In addition, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from coronavirus disease 2019 (COVID-19) patients. The rates of SARS-CoV-2-infected monocytes in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients increased over time from symptom onset, with SARS-CoV-2-positive monocytes, B cells, and CD4+ T lymphocytes also detected in post mortem lung tissue. These results indicated that SARS-CoV-2 infection of blood circulating leukocytes in COVID-19 patients might have important implications for disease pathogenesis and progression, immune dysfunction, and virus spread within the host.

Intracellular pattern recognition receptors such as the nucleotide-binding oligomerization domain (NOD)-like receptors family members are key for innate immune recognition of microbial infection and may play important roles in the development of inflammatory diseases, including rheumatic diseases. In this study, we evaluated the role of NOD1 and NOD2 on development of experimental arthritis. Ag-induced arthritis was generated in wild-type, NOD1−/−, NOD2−/−, or receptor-interacting serine-threonine kinase 2−/− (RIPK2−/−) immunized mice challenged intra-articularly with methylated BSA. Nociception was determined by electronic Von Frey test. Neutrophil recruitment and histopathological analysis of proteoglycan lost was evaluated in inflamed joints. Joint levels of inflammatory cytokine/chemokine were measured by ELISA. Cytokine (IL-6 and IL-23) and NOD2 expressions were determined in mice synovial tissue by RT-PCR. The NOD2−/− and RIPK2−/−, but not NOD1−/−, mice are protected from Ag-induced arthritis, which was characterized by a reduction in neutrophil recruitment, nociception, and cartilage degradation. NOD2/RIPK2 signaling impairment was associated with a reduction in proinflammatory cytokines and chemokines (TNF, IL-1β, and CXCL1/KC). IL-17 and IL-17 triggering cytokines (IL-6 and IL-23) were also reduced in the joint, but there is no difference in the percentage of CD4+ IL-17+ cells in the lymph node between arthritic wild-type and NOD2−/− mice. Altogether, these findings point to a pivotal role of the NOD2/RIPK2 signaling in the onset of experimental arthritis by triggering an IL-17–dependent joint immune response. Therefore, we could propose that NOD2 signaling is a target for the development of new therapies for the control of rheumatoid arthritis.

Há uma crescente literatura empírica documentando que educação e cuidado parental de qualidade estão associados com um melhor desenvolvimento emocional e cognitivo da criança. Diante disso, governos de vários países vêm promovendo mudanças nas suas leis trabalhistas, com o objetivo de dar suporte financeiro e legal (proteção do emprego) para as mães e também os pais com crianças recém-nascidas. O Brasil aprovou recentemente o Marco Legal da Primeira Infância (Lei n. 13.257/2016), que ampliou a licença-paternidade de 5 para 20 dias. Pouco  se sabe, entretanto, sobre o impacto econômico desse tipo de política pública. O presente trabalho procura quantificar os custos intertemporais do custo econômico direto da extensão da licença-paternidade para o Brasil. Para isso utilizam-se microdados da Pesquisa Nacional por Amostra de Domicílios, indicadores do mercado de trabalho brasileiro e uma série de projeções populacionais para construir cenários estáticos para estimativas da probabilidade de os pais solicitarem o uso da licença. Os resultados indicam que a extensão da licença-paternidade para 20 dias tem baixo custo – cerca de R$ 100 milhões por ano no cenário mais provável, o que representa 0,01% da arrecadação federal em 2014. Conquanto a magnitude dos benefícios seja ainda desconhecida no Brasil, os resultados sugerem que esse tipo de intervenção será provavelmente custo-efetiva.