Program of Immunology and Cellular Biology, Department of Biology, Georgia State University, Atlanta, GA 30302; and.
Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302.
J Immunol. 2020 Nov 15;205(10):2821-2833. doi: 10.4049/jimmunol.2000652. Epub 2020 Oct 7.
A hallmark of secondary hemophagocytic lymphohistiocytosis (sHLH), a severe form of cytokine storm syndrome, is the emergence of overactivated macrophages that engulf healthy host blood cells (i.e., hemophagocytosis) and contribute to the dysregulated inflammation-driven pathology. In this study, we show that depleting SIRPα (SIRPα) in mice during TLR9-driven inflammation exacerbates and accelerates the onset of fulminant sHLH, in which systemic hemophagocytosis, hypercytokinemia, consumptive cytopenias, hyperferritinemia, and other hemophagocytic lymphohistiocytosis hallmarks were apparent. In contrast, mice expressing SIRPα, including those deficient of the SIRPα ligand CD47 (CD47), do not phenocopy SIRPα deficiency and fail to fully develop sHLH, albeit TLR9-inflamed wild-type and CD47 mice exhibited hemophagocytosis, anemia, and splenomegaly. Although IFN-γ is largely considered a driver of hemophagocytic lymphohistiocytosis pathology, IFN-γ neutralization did not preclude the precipitation of sHLH in TLR9-inflamed SIRPα mice, whereas macrophage depletion attenuated sHLH in SIRPα mice. Mechanistic studies confirmed that SIRPα not only restrains macrophages from acquiring a hemophagocytic phenotype but also tempers their proinflammatory cytokine and ferritin secretion by negatively regulating Erk1/2 and p38 activation downstream of TLR9 signaling. In addition to TLR9 agonists, TLR2, TLR3, or TLR4 agonists, as well as TNF-α, IL-6, or IL-17A, but not IFN-γ, similarly induced sHLH in SIRPα mice but not SIRPα mice. Collectively, our study suggests that SIRPα plays a previously unappreciated role in sHLH/cytokine storm syndrome pathogenesis by preventing macrophages from becoming both hemophagocytic and hyperactivated under proinflammation.
继发性噬血细胞性淋巴组织细胞增生症（sHLH）是细胞因子风暴综合征的一种严重形式，其特征是出现过度激活的巨噬细胞吞噬健康宿主血细胞（即噬血细胞现象），并导致失调的炎症驱动的病理。在这项研究中，我们表明，在 TLR9 驱动的炎症期间耗尽 SIRPα（SIRPα）会加剧和加速致命性 sHLH 的发作，其中明显出现全身噬血细胞现象、细胞因子血症、消耗性血细胞减少症、高铁蛋白血症和其他噬血细胞性淋巴组织细胞增生症特征。相比之下，表达 SIRPα的小鼠，包括 SIRPα配体 CD47（CD47）缺陷的小鼠，不会表现出 SIRPα 缺陷的表型，也不能完全发展为 sHLH，尽管 TLR9 炎症的野生型和 CD47 小鼠表现出噬血细胞现象、贫血和脾肿大。虽然 IFN-γ 被广泛认为是噬血细胞性淋巴组织细胞增生症病理的驱动因素，但 IFN-γ 中和并不能阻止 TLR9 炎症的 SIRPα 小鼠发生 sHLH，而巨噬细胞耗竭则减轻了 SIRPα 小鼠的 sHLH。机制研究证实，SIRPα 不仅阻止巨噬细胞获得噬血细胞表型，而且通过负向调节 TLR9 信号下游的 Erk1/2 和 p38 激活来调节其促炎细胞因子和铁蛋白分泌。除 TLR9 激动剂外，TLR2、TLR3 或 TLR4 激动剂以及 TNF-α、IL-6 或 IL-17A，但不是 IFN-γ，同样在 SIRPα 小鼠中诱导 sHLH，但不在 SIRPα 小鼠中诱导。总之，我们的研究表明，SIRPα 通过防止巨噬细胞在炎症前既成为噬血细胞又过度激活，在 sHLH/细胞因子风暴综合征发病机制中发挥了以前未被认识的作用。
