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C5aR2 Activation Broadly Modulates the Signaling and Function of Primary Human Macrophages
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-07-01 , DOI: 10.4049/jimmunol.2000407
Xaria X Li 1 , Richard J Clark 1 , Trent M Woodruff 2
Affiliation  

Key Points C5aR2 agonism dampens C5aR1-, C3aR-, and CMKLR1-mediated ERK signaling in macrophages. C5aR2 agonism modulates C5aR1-, C3aR-, and LTB4R-mediated calcium mobilization. C5aR2 activation downregulates TLRs 3, 4, 7, Mincle-, and STING-mediated cytokines. Visual Abstract The complement activation fragment C5a is a potent proinflammatory mediator that is increasingly recognized as an immune modulator. C5a acts through two C5a receptors, C5aR1 (C5aR, CD88) and C5aR2 (C5L2, GPR77), to powerfully modify multiple aspects of immune cell function. Although C5aR1 is generally acknowledged to be proinflammatory and immune-activating, the potential roles played by C5aR2 remain poorly defined. Despite studies demonstrating C5aR2 can modulate C5aR1 in human cells, it is not yet known whether C5aR2 functionality is limited to, or requires, C5aR1 activation or influences immune cells more broadly. The present study, therefore, aimed to characterize the roles of C5aR2 on the signaling and function of primary human monocyte–derived macrophages, using a C5aR2 agonist (Ac-RHYPYWR-OH; P32) to selectively activate the receptor. We found that although C5aR2 activation with P32 by itself was devoid of any detectable MAPK signaling activities, C5aR2 agonism significantly dampened C5aR1-, C3aR-, and chemokine-like receptor 1 (CMKLR1)–mediated ERK signaling and altered intracellular calcium mobilization mediated by these receptors. Functionally, selective C5aR2 activation also downregulated cytokine production triggered by various TLRs (TLR2, TLR3, TLR4, and TLR7), C-type lectin receptors (Dectin-1, Dectin-2, and Mincle), and the cytosolic DNA sensor stimulator of IFN genes (STING). Surprisingly, activity at the C-type lectin receptors was particularly powerful, with C5aR2 activation reducing Mincle-mediated IL-6 and TNF-α generation by 80–90%. In sum, this study demonstrates that C5aR2 possesses pleiotropic functions in primary human macrophages, highlighting the role of C5aR2 as a powerful regulator of innate immune function.

中文翻译:

C5aR2 激活广泛调节原代人类巨噬细胞的信号传导和功能

关键点 C5aR2 激动抑制巨噬细胞中 C5aR1-、C3aR- 和 CMKLR1 介导的 ERK 信号传导。C5aR2 激动作用调节 C5aR1-、C3aR- 和 LTB4R 介导的钙动员。C5aR2 激活下调 TLR 3、4、7、Mincle 和 STING 介导的细胞因子。视觉摘要 补体激活片段 C5a 是一种有效的促炎介质,越来越多地被认为是一种免疫调节剂。C5a 通过两个 C5a 受体 C5aR1(C5aR、CD88)和 C5aR2(C5L2、GPR77)发挥作用,以强有力地改变免疫细胞功能的多个方面。尽管 C5aR1 被普遍认为是促炎和免疫激活的,但 C5aR2 所发挥的潜在作用仍然不明确。尽管研究表明 C5aR2 可以调节人类细胞中的 C5aR1,但尚不清楚 C5aR2 的功能是否仅限于或需要,C5aR1 激活或更广泛地影响免疫细胞。因此,本研究旨在通过使用 C5aR2 激动剂(Ac-RHYPYWR-OH;P32)选择性激活受体来表征 C5aR2 对原代人单核细胞衍生巨噬细胞的信号传导和功能的作用。我们发现,虽然 C5aR2 用 P32 激活本身没有任何可检测的 MAPK 信号活动,但 C5aR2 激动显着抑制了 C5aR1-、C3aR- 和趋化因子样受体 1 (CMKLR1) 介导的 ERK 信号传导,并改变了由这些介导的细胞内钙动员受体。在功能上,选择性 C5aR2 激活还下调由各种 TLR(TLR2、TLR3、TLR4 和 TLR7)、C 型凝集素受体(Dectin-1、Dectin-2 和 Mincle)和 IFN 的细胞溶质 DNA 传感器刺激物触发的细胞因子产生基因(STING)。令人惊讶的是,C 型凝集素受体的活性特别强大,C5aR2 激活使 Mincle 介导的 IL-6 和 TNF-α 生成减少了 80-90%。总之,这项研究表明 C5aR2 在原代人类巨噬细胞中具有多效性,突出了 C5aR2 作为先天免疫功能的强大调节剂的作用。
更新日期:2020-07-01
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