坏死性下垂
炎症体
炎症
程序性细胞死亡
肺
CD8型
免疫学
Fas配体
细胞因子
干扰素
细胞凋亡
细胞毒性T细胞
生物
医学
免疫系统
内科学
生物化学
体外
作者
Yoji Komiya,Mari Kamiya,Seiya Oba,Daisuke Kawata,Hideyuki Iwai,Hiroshi Shintaku,Yoshio Suzuki,Sho Miyamoto,Minoru Tobiume,Takayuki Kanno,Akira Ainai,Tadaki Suzuki,Hideki Hasegawa,Tadashi Hosoya,Shinsuke Yasuda
标识
DOI:10.1016/j.bbadis.2024.167472
摘要
COVID-19, caused by SARS-CoV-2 infection, results in irreversible or fatal lung injury. We assumed that necroptosis of virus-infected alveolar epithelial cells (AEC) could promote local inflammation and further lung injury in COVID-19. Since CD8+ lymphocytes induced AEC cell death via cytotoxic molecules such as FAS ligands, we examined the involvement of FAS-mediated cell death in COVID-19 patients and murine COVID-19 model. We identified the occurrence of necroptosis and subsequent release of HMGB1 in the admitted patients with COVID-19. In the mouse model of COVID-19, lung inflammation and injury were attenuated in Fas-deficient mice compared to Fas-intact mice. The infection enhanced Type I interferon-inducible genes in both groups, while inflammasome-associated genes were specifically upregulated in Fas-intact mice. The treatment with necroptosis inhibitor, Nec1s, improved survival rate, lung injury, and systemic inflammation. SARS-CoV-2 induced necroptosis causes cytokine induction and lung damage, and its inhibition could be a novel therapeutic strategy for COVID-19.
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