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.

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。尽管在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，但我们发现只有TNF-α和IFN-γ的组合才能诱导以炎症细胞死亡，PANoptosis为特征的炎症细胞死亡。从机制上讲，TNF-α和IFN-γ共同处理可激活JAK / STAT1 / IRF1轴，诱导产生一氧化氮并驱动caspase-8 / FADD介导的PAN凋亡。TNF-α和IFN-γ在小鼠中引起致命的细胞因子休克，反映出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的中和抗体治疗可保护小鼠免受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，我们的发现表明，阻断此处确定的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。