The C5a/C5aR2 axis promotes renal inflammation and tissue damage
The C5a/C5aR2 axis promotes renal inflammation and tissue damage
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C5a/C5aR2 轴促进肾脏炎症和组织损伤
DOI：
10.1172/jci.insight.134081
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发表时间：
2020
期刊：
影响因子：
8
通讯作者：
Ke Li
中科院分区：
文献类型：
--
作者：
Ting Zhang;Kun-yi Wu;Ning Ma;Ling-lin Wei;Malgorzata Garstka;Wuding Zhou;Ke Li
C5a是一种结合C5aR1和C5aR2的有效炎症介质。尽管C5a/C5aR1轴在炎症性疾病中的致病作用已被充分证实，但C5a/C5aR2轴在炎症性疾病中的作用及其潜在机制尚不清楚。在这里，我们发现C5a/C5aR2轴在急性肾盂肾炎小鼠模型中参与肾脏炎症和组织损伤。与WT同窝小鼠相比，C5ar2 - / -小鼠在膀胱接种尿路致病性大肠杆菌后，肾脏炎症、肾小管损伤和肾脏细菌负荷显著减少。C5ar2 - / -小鼠肾脏炎症反应的降低与肾内高迁移率组盒-1蛋白（HMGB1）、NLRP3炎性小体成分、cleaved caspase-1和IL-1β水平的降低有关。在体外，C5ar1 - / -小鼠巨噬细胞（缺乏C5ar1但表达C5aR2）的C5a刺激导致HMGB1释放、NLRP3/cleaved caspase-1炎性体激活和IL-1β分泌显著上调。此外，阻断HMGB1可显著降低c5a介导的巨噬细胞中NLRP3/cleaved caspase-1炎性体激活和IL-1β分泌的上调，这意味着巨噬细胞中NLRP3/cleaved caspase-1炎性体激活的上调依赖于HMGB1。我们的研究结果证明了C5a/C5aR2轴在肾脏感染后肾损伤中的致病作用，并表明C5a/C5aR2轴通过上调HMGB1和NLRP3/cleaved caspase-1炎性体参与肾脏炎症和组织损伤。
C5a is a potent inflammatory mediator that binds C5aR1 and C5aR2. Although pathogenic roles of the C5a/C5aR1 axis in inflammatory disorders are well documented, the roles for the C5a/C5aR2 axis in inflammatory disorders and underlying mechanisms remain unclear. Here, we show that the C5a/C5aR2 axis contributes to renal inflammation and tissue damage in a mouse model of acute pyelonephritis. Compared with WT littermates, C5ar2–/– mice had significantly reduced renal inflammation, tubular damage, and renal bacterial load following bladder inoculation with uropathogenic E. coli. The decrease in inflammatory responses in the kidney of C5ar2–/– mice was correlated with reduced intrarenal levels of high mobility group box-1 protein (HMGB1), NLRP3 inflammasome components, cleaved caspase-1, and IL-1β. In vitro, C5a stimulation of macrophages from C5ar1–/– mice (lacking C5aR1 but expressing C5aR2) led to significant upregulation of HMGB1 release, NLRP3/cleaved caspase-1 inflammasome activation, and IL-1β secretion. Furthermore, blockade of HMGB1 significantly reduced C5a-mediated upregulation of NLRP3/cleaved caspase-1 inflammasome activation and IL-1β secretion in the macrophages, implying a HMGB1-dependent upregulation of NLRP3/cleaved caspase-1 inflammasome activation in macrophages. Our findings demonstrate a pathogenic role for the C5a/C5aR2 axis in renal injury following renal infection and suggest that the C5a/C5aR2 axis contributes to renal inflammation and tissue damage through upregulation of HMGB1 and NLRP3/cleaved caspase-1 inflammasome.