Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA.
Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA
J Immunol. 2021 Sep 1;207(5):1419-1427. doi: 10.4049/jimmunol.2100266. Epub 2021 Aug 4.
Macrophage functional plasticity plays a central role in responding to proinflammatory stimuli. The molecular basis underlying the dynamic phenotypic activation of macrophages, however, remains incompletely understood. In this article, we report that SIRPα is a chief negative regulator of proinflammatory macrophage polarization. In response to TLR agonists, proinflammatory cytokines, or canonical M1 stimulation, Src family kinases (SFK) excluding Lyn phosphorylate SIRPα ITIMs, leading to the preferential recruitment and activation of SHP-1, but not SHP-2. Solely extracellular ligation of SIRPα by CD47 does not greatly induce phosphorylation of SIRPα ITIMs, but it enhances proinflammatory stimuli-induced SIRPα phosphorylation. Examination of downstream signaling elicited by IFN-γ and TLR3/4/9 agonists found that SIRPα-activated SHP-1 moderately represses STAT1, NF-κB, and MAPK signaling but markedly inhibits Akt2, resulting in dampened proinflammatory cytokine production and expression of Ag presentation machinery. Pharmacological inhibition of SHP-1 or deficiency of SIRPα conversely attenuates SIRPα-mediated inhibition and, as such, augments macrophage proinflammatory polarization that in turn exacerbates proinflammation in mouse models of type I diabetes and peritonitis. Our results reveal an SFK-SIRPα-SHP-1 mechanism that fine-tunes macrophage proinflammatory phenotypic activation via inhibition of PI3K-Akt2, which controls the transcription and translation of proinflammatory cytokines, Ag presentation machinery, and other cellular programs.
巨噬细胞功能可塑性在应对促炎刺激中起着核心作用。然而，巨噬细胞动态表型激活的分子基础仍不完全清楚。本文报道 SIRPα 是促炎巨噬细胞极化的主要负调控因子。在 TLR 激动剂、促炎细胞因子或经典 M1 刺激下，Src 家族激酶（SFK）除 Lyn 外，磷酸化 SIRPα ITIM，导致 SHP-1 的优先募集和激活，但不是 SHP-2。CD47 仅对 SIRPα 的细胞外结合不会大大诱导 SIRPα ITIM 的磷酸化，但它增强了促炎刺激诱导的 SIRPα 磷酸化。对 IFN-γ 和 TLR3/4/9 激动剂引发的下游信号的研究发现，SIRPα 激活的 SHP-1 适度抑制 STAT1、NF-κB 和 MAPK 信号，但显著抑制 Akt2，导致促炎细胞因子产生和抗原呈递机制的表达减少。SHP-1 的药理学抑制或 SIRPα 的缺乏相反地减弱了 SIRPα 介导的抑制作用，从而增强了巨噬细胞的促炎极化，进而加剧了 I 型糖尿病和腹膜炎小鼠模型中的促炎反应。我们的结果揭示了一种 SFK-SIRPα-SHP-1 机制，通过抑制 PI3K-Akt2 来微调巨噬细胞的促炎表型激活，该机制控制促炎细胞因子、抗原呈递机制和其他细胞程序的转录和翻译。
