RESUMO
BACKGROUND: The transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp-1) has a key role in terminal differentiation in various T-cell subtypes. However, whether Blimp-1 regulates TH9 differentiation and its role in allergic inflammation are unknown. OBJECTIVE: We aimed to investigate the role of Blimp-1 in TH9 differentiation and in the pathogenesis of allergic airway inflammation. METHODS: In vitro TH9 differentiation, flow cytometry, ELISA, and real-time PCR were used to investigate the effects of Blimp-1 on TH9 polarization. T cell-specific Blimp-1-deficient mice, a model of allergic airway inflammation, and T-cell adoptive transfer to recombination-activating gene 1 (Rag-1)-/- mice were used to address the role of Blimp-1 in the pathogenesis of allergic inflammation. RESULTS: We found that Blimp-1 regulates TH9 differentiation because deleting Blimp-1 increased IL-9 production in CD4+ T cells in vitro. In addition, we showed that in T cell-specific Blimp-1-deficient mice, deletion of Blimp-1 in T cells worsened airway disease, and this worsening was inhibited by IL-9 neutralization. In asthmatic patients CD4+ T cells in response to TGF-ß plus IL-4 increased IL-9 expression and downregulated Blimp-1 expression compared with expression in healthy control subjects. Blimp-1 overexpression in human TH9 cells inhibited IL-9 expression. CONCLUSION: Blimp-1 is a pivotal negative regulator of TH9 differentiation and controls allergic inflammation.
Assuntos
Asma/imunologia , Diferenciação Celular , Interleucina-9/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/fisiologia , Linfócitos T Auxiliares-Indutores/fisiologia , Animais , Linhagem Celular , Humanos , Inflamação/imunologia , Interleucina-9/genética , Camundongos TransgênicosRESUMO
Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. 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 represents a potential therapeutic target for COVID-19.
Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/fisiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células A549 , Adulto , Enzima de Conversão de Angiotensina 2 , COVID-19 , Morte Celular , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Feminino , Células HeLa , Humanos , Masculino , Ativação de Neutrófilo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/sangue , Pneumonia Viral/patologia , SARS-CoV-2 , Serina Proteases/metabolismo , Sucção , Traqueia/imunologiaRESUMO
In the past years, extracellular vesicles (EVs) have become an important field of research since EVs have been found to play a central role in biological processes. In pathogens, EVs are involved in several events during the host-pathogen interaction, including invasion, immunomodulation, and pathology as well as parasite-parasite communication. In this report, we summarised the role of EVs in infections caused by viruses, bacteria, fungi, protozoa, and helminths based on the talks and discussions carried out during the International Society for Extracellular Vesicles (ISEV) workshop held in São Paulo (November, 2016), Brazil, entitled Cross-organism Communication by Extracellular Vesicles: Hosts, Microbes and Parasites.