Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.
Max Planck Institute of Biochemistry, Martinsried, Planegg, Germany.
Cell Death Differ. 2022 Feb;29(2):420-438. doi: 10.1038/s41418-021-00866-0. Epub 2021 Sep 13.
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.
炎症反应能够迅速检测到病原体的入侵，并引发一种受调控的反应。然而，抗病原体免疫反应失调会引发危及生命的炎症性病理，统称为细胞因子释放综合征（CRS），在 SARS-CoV-2 大流行期间发现了关键的临床表型。CRS 的潜在病理生理学仍然难以捉摸。我们发现，FLIP，一种控制半胱天冬酶-8 死亡途径的蛋白质，在 COVID-19 肺部的髓样细胞中高度表达。FLIP 通过推动 STAT3 依赖性炎症程序来控制 CRS。事实上，髓样细胞中组成性表达病毒 FLIP 同源物会引发一种 STAT3 相关的、进行性的、致命的炎症综合征，其特征是细胞因子输出增加、淋巴细胞减少、肺损伤和多器官功能障碍，这些都模拟了人类 CRS。由于针对 STAT3 的治疗方法缓解了这些小鼠的炎症、免疫紊乱和器官衰竭，因此针对该途径的靶向干预可能会抑制致命的 CRS 炎症状态。
