The C5a/C5aR2 axis promotes renal inflammation and tissue damage
Ting Zhang, … , Wuding Zhou, Ke Li
Ting Zhang, … , Wuding Zhou, Ke Li
Published March 19, 2020
Citation Information: JCI Insight. 2020;5(7):e134081. https://doi.org/10.1172/jci.insight.134081.
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Research Article Inflammation Nephrology

The C5a/C5aR2 axis promotes renal inflammation and tissue damage

Abstract

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.

Authors

Ting Zhang, Kun-yi Wu, Ning Ma, Ling-lin Wei, Malgorzata Garstka, Wuding Zhou, Ke Li

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Figure 2

C5ar2–/– mice have reduced inflammatory responses in the kidney following inoculation with UPEC.

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C5ar2–/– mice have reduced inflammatory responses in the kidney followi...
(A and B) Quantification of inflammatory cells in infected kidney tissues of WT and C5ar2–/– mice at 24 hpi, determined by flow cytometry. The gating strategy of analyzing inflammatory cells by flow cytometry was given in Supplemental Figure 1A. The dotted line across each graph represents the level of inflammatory cells in normal kidney tissue, which is similar between WT and C5ar2–/– mice. Data were analyzed by unpaired 2-tailed Student’s t test (n = 10 mice/group). (C) Cytokine levels in the infected kidney tissues of WT and C5ar2–/– mice at 24 hpi, determined by ELISA. The dotted line across each graph represents the level of cytokines in normal kidney tissue, which is similar between WT and C5ar2–/– mice. Data were analyzed by 2-way ANOVA with multiple comparisons test (n = 10 mice/group). Data are shown as mean ± SD. *P < 0.05, **P < 0.005, ****P < 0.0001. Mo/MΦ, monocyte/macrophage.