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Cell Death Differ ; 29(2): 420-438, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34518653

RESUMO

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.


Assuntos
COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/metabolismo , Inflamação/metabolismo , Fator de Transcrição STAT3/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , COVID-19/metabolismo , Caspase 8/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Fator de Transcrição STAT3/genética , Transdução de Sinais
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