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.

炎症反应可快速检测病原体入侵并启动调节反应。然而，失调的抗病原体免疫反应会引发危及生命的炎症病理，统称为细胞因子释放综合征 (CRS)，例如 SARS-CoV-2 大流行期间发现的关键临床表型。CRS 的潜在病理生理学仍然难以捉摸。我们发现 FLIP 是一种控制 caspase-8 死亡途径的蛋白质，它在 COVID-19 肺的骨髓细胞中高表达。FLIP 通过促进 STAT3 依赖性炎症程序来控制 CRS。事实上，骨髓细胞中病毒 FLIP 同系物的组成型表达在小鼠中引发了 STAT3 相关的、进行性和致命的炎症综合征，其特征是细胞因子输出升高、淋巴细胞减少、肺损伤、以及模仿人类 CRS 的多器官功能障碍。由于 STAT3 靶向方法减轻了这些小鼠的炎症、免疫紊乱和器官衰竭，因此对该通路的靶向干预可以抑制致命的 CRS 炎症状态。