美国圣犹大儿童研究医院Thirumala-Devi Kanneganti团队发现，在SARS-CoV-2感染和细胞因子休克综合征中，TNF-α和IFN-γ的协同作用可引发炎性细胞死亡、组织损伤以及死亡率。2020年11月18日，《细胞》杂志在线发表了这一最新研究成果。

虽然在SARS-CoV-2感染过程中先天免疫细胞会产生多种炎症细胞因子，但研究人员发现只有TNF-α和IFN-γ的组合才能诱导炎症细胞死亡，其特征为焦亡、凋亡和坏死（PANoptosis）。从机制上讲，TNF-α和IFN-γ共同处理可激活JAK/STAT1/IRF1信号轴，诱导产生一氧化氮并驱动caspase-8/FADD介导的PANoptosis。TNF-α和IFN-γ在小鼠中引起致命的细胞因子休克，这反映了COVID-19的组织损伤和炎症，并抑制PANoptosis保护了小鼠免于这种病理和死亡。

此外，用抗TNF-α和IFN-γ的中和抗体处理可保护小鼠免受SARS-CoV-2感染、败血症、吞噬性淋巴细胞组织细胞增生和细胞因子休克期间的死亡。

总体而言，这些发现表明，阻断这些细胞因子介导的炎性细胞死亡信号通路可能会通过限制组织损伤/炎症而使COVID-19或其他感染性和自身炎性疾病的患者受益。

据介绍，COVID-19的特征是促炎性细胞因子的过量产生以及与患者死亡率相关的急性肺损伤。

附：英文原文

Title: Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes

Author: Rajendra Karki, Bhesh Raj Sharma, Shraddha Tuladhar, Evan Peter Williams, Lillian Zalduondo, Parimal Samir, Min Zheng, Balamurugan Sundaram, Balaji Banoth, R. K. Subbarao Malireddi, Patrick Schreiner, Geoffrey Neale, Peter Vogel, Richard Webby, Colleen Beth Jonsson, Thirumala-Devi Kanneganti

Issue&Volume: 2020-11-18

Abstract: 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 pyroptosis, apoptosis, and necroptosis (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.

DOI: 10.1016/j.cell.2020.11.025

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31542-7