Huarte Eduardo, Peel Michael T, Verbist Katherine, Fay Brittany L, Bassett Rachel, Albeituni Sabrin, Nichols Kim E, Smith Paul A
Incyte Research Institute, Wilmington, DE, United States.
St. Jude Children's Research Hospital, Memphis, TN, United States.
Front Pharmacol. 2021 Apr 22;12:650295. doi: 10.3389/fphar.2021.650295. eCollection 2021.
Hyperinflammatory syndromes comprise a heterogeneous group of disorders characterized by severe inflammation, multiple organ dysfunction, and potentially death. In response to antigenic stimulus (e.g., SARS-CoV-2 infection), overactivated CD8+ T-cells and macrophages produce high levels of proinflammatory cytokines, such as IFN-γ, TNF-α, IL-6, and IL-12. Multiple inflammatory mediators implicated in hyperinflammatory syndromes utilize the Janus kinase-signal transducers and activators of transcription (JAK-STAT) cascade to propagate their biological function. Our findings demonstrate that oral ruxolitinib dosing designed to mimic clinically relevant JAK-STAT pathway inhibition significantly reduces the harmful consequences of immune overactivation in multiple hyperinflammatory models. In contrast to monoclonal antibody therapies targeting a single cytokine, ruxolitinib effectively downregulates the functional effect of multiple cytokines implicated in hyperinflammatory states, without broad immunosuppression.
高炎症综合征是一组异质性疾病，其特征为严重炎症、多器官功能障碍，并可能导致死亡。针对抗原刺激（如严重急性呼吸综合征冠状病毒2感染），过度活化的CD8+T细胞和巨噬细胞会产生高水平的促炎细胞因子，如干扰素-γ、肿瘤坏死因子-α、白细胞介素-6和白细胞介素-12。高炎症综合征中涉及的多种炎症介质利用Janus激酶-信号转导子和转录激活子（JAK-STAT）级联来发挥其生物学功能。我们的研究结果表明，旨在模拟临床相关JAK-STAT通路抑制的口服鲁索替尼给药可显著减轻多种高炎症模型中免疫过度激活的有害后果。与靶向单一细胞因子的单克隆抗体疗法不同，鲁索替尼可有效下调高炎症状态下多种细胞因子的功能效应，而不会导致广泛的免疫抑制。
