The complement receptor C5aR2 promotes protein kinase R expression and contributes to NLRP3 inflammasome activation and HMGB1 release from macrophages
The complement receptor C5aR2 promotes protein kinase R expression and contributes to NLRP3 inflammasome activation and HMGB1 release from macrophages
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补体受体 C5aR2 促进蛋白激酶 R 表达，并有助于 NLRP3 炎性体激活和巨噬细胞释放 HMGB1
DOI：
10.1074/jbc.ra118.006508
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发表时间：
2019-04
影响因子：
4.8
通讯作者：
Lu Ben
中科院分区：
文献类型：
--
作者：
Yu Songlin;Wang Dan;Huang Lingmin;Zhang Yening;Luo Ruiheng;Adah Dickson;Tang Yiting;Zhao Kai;Lu Ben
NLR 家族包含热蛋白结构域 3 (NLRP3) 的炎症小体是一种多聚蛋白复合物，可介导细胞因子 IL-1β 和 IL-18 的成熟以及促炎蛋白高迁移率族蛋白 1 (HMGB1) 的释放，并导致多种炎症疾病，包括败血症、痛风和 2 型糖尿病。在这种情况下，经过充分研究的活性补体片段 C5a 及其受体 C5aR1 或 C5aR2 协调许多疾病中的炎症反应。尽管C5a-C5aR在NLRP3相关疾病中存在相互作用，但人们对C5a-C5aR与巨噬细胞中NLRP3炎性小体相互作用的细节知之甚少。在这项研究中，我们使用小鼠和鼠巨噬细胞和细胞因子、免疫印迹、siRNA 和定量实时 PCR 测定，证明 C5aR2 缺陷在体外和体内限制了 NLRP3 炎性体的激活和 HMGB1 的释放。从机制上讲，我们发现C5aR2通过放大dsRNA依赖性PKR表达来促进NLRP3激活，PKR是重要的NLRP3激活因子。我们还观察到，由于 C5a-C5aR2 相互作用而引起的 PKR 表达升高取决于丝裂原激活蛋白激酶/细胞外信号调节激酶激酶途径和 I 型 IFN 信号传导。总之，这些发现表明 C5aR2 有助于 NLRP3 炎性体激活和巨噬细胞释放 HMGB1。
The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a multimeric protein complex that mediates maturation of the cytokines IL-1β and IL-18 as well as release of the proinflammatory protein high-mobility group box 1 (HMGB1) and contributes to several inflammatory diseases, including sepsis, gout, and type 2 diabetes. In this context, the well-studied active complement fragment C5a and its receptor C5aR1 or C5aR2 orchestrate the inflammatory responses in many diseases. Although a C5a-C5aR interaction in NLRP3-associated diseases has been suggested, little is known about the details of C5a–C5aR cross-talk with the NLRP3 inflammasome in macrophages. In this study, using mice and murine macrophages and cytokines, immunoblotting, siRNA, and quantitative real-time PCR assays, we demonstrate that C5aR2 deficiency restricts activation of the NLRP3 inflammasome and release of HMGB1 both in vitro and in vivo. Mechanistically, we found that C5aR2 promotes NLRP3 activation by amplifying dsRNA-dependent PKR expression, which is an important NLRP3-activating factor. We also observed that elevation of PKR expression because of the C5a–C5aR2 interaction depends on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase pathway and type I IFN signaling. In conclusion, these findings reveal that C5aR2 contributes to NLRP3 inflammasome activation and HMGB1 release from macrophages.
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影响因子：
64.5
作者：
Dey, M;Cao, C;Dever, TE
通讯作者：
Dever, TE
有争议的 C5a 受体 C5aR2：其在健康和疾病中的作用
影响因子：
4.1
作者：
Zhang Ting;Garstka Malgorzata A.;Li Ke
通讯作者：
Li Ke
影响因子：
4.6
作者：
Haggadone MD;Grailer JJ;Fattahi F;Zetoune FS;Ward PA
通讯作者：
Ward PA
影响因子：
64.5
作者：
ROUSE, J;COHEN, P;NEBREDA, AR
通讯作者：
NEBREDA, AR
影响因子：
16
作者：
Walker, EH;Pacold, ME;Williams, RL
通讯作者：
Williams, RL