Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes.
Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes.
复制标题
在SARS-CoV-2感染和细胞因子休克综合征中，TNF-α和IFN-γ的协同作用引发炎症细胞死亡、组织损伤和死亡率。
DOI：
10.1016/j.cell.2020.11.025
复制
发表时间：
2021-01-07
期刊：
影响因子：
64.5
通讯作者：
Kanneganti TD
中科院分区：
文献类型：
--
作者：
Karki R;Sharma BR;Tuladhar S;Williams EP;Zalduondo L;Samir P;Zheng M;Sundaram B;Banoth B;Malireddi RKS;Schreiner P;Neale G;Vogel P;Webby R;Jonsson CB;Kanneganti TD
COVID-19的特征是促炎细胞因子的过度产生和与患者死亡相关的急性肺损伤。虽然SARS-CoV-2感染过程中天然免疫细胞产生多种炎性细胞因子，但我们发现只有TNF-α和IFN-γ联合诱导的炎性细胞死亡以炎性细胞死亡（PAN凋亡）为特征。从机制上讲，TNF-α和IFN-γ共同处理激活JAK/STAT 1/IRF 1轴，诱导一氧化氮产生并驱动caspase-8/FADD介导的PANoptosis。TNF-α和IFN-γ在小鼠中引起致死性细胞因子休克，反映了COVID-19的组织损伤和炎症，抑制PAN细胞凋亡可保护小鼠免受这种病理和死亡。此外，用抗TNF-α和IFN-γ的中和抗体治疗可以保护小鼠在SARS-CoV-2感染、脓毒症、噬血细胞性淋巴组织细胞增多症和细胞因子休克期间免于死亡。总的来说，我们的研究结果表明，阻断此处确定的烟碱介导的炎性细胞死亡信号通路可能通过限制组织损伤/炎症而使COVID-19或其他感染性和自身炎性疾病患者受益。TNF-α和IFN-γ协同驱动与COVID-19和脓毒症相关的细胞因子风暴和细胞死亡。
COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by inflammatory cell death, PANoptosis. Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation. TNF-α and IFN-γ synergize to drive the cytokine storm and cell death associated with COVID-19 and sepsis.
登录
查看更多内容
影响因子：
8.8
作者：
Dillon CP;Oberst A;Weinlich R;Janke LJ;Kang TB;Ben-Moshe T;Mak TW;Wallach D;Green DR
通讯作者：
Green DR
影响因子：
9
作者：
Channappanavar R;Perlman S
通讯作者：
Perlman S
影响因子：
5.8
作者：
Brubaker SW;Brewer SM;Massis LM;Napier BA;Monack DM
通讯作者：
Monack DM
影响因子：
82.9
作者：
Del Valle DM;Kim-Schulze S;Huang HH;Beckmann ND;Nirenberg S;Wang B;Lavin Y;Swartz TH;Madduri D;Stock A;Marron TU;Xie H;Patel M;Tuballes K;Van Oekelen O;Rahman A;Kovatch P;Aberg JA;Schadt E;Jagannath S;Mazumdar M;Charney AW;Firpo-Betancourt A;Mendu DR;Jhang J;Reich D;Sigel K;Cordon-Cardo C;Feldmann M;Parekh S;Merad M;Gnjatic S
通讯作者：
Gnjatic S
影响因子：
13.8
作者：
Damsky W;King BA
通讯作者：
King BA