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The C3a/C3aR axis mediates anti-inflammatory activity and protects against uropathogenic E coli–induced kidney injury in mice

Research output: Contribution to journalArticlepeer-review

Kun-yi Wu, Ting Zhang, Guo-xiu Zhao, Ning Ma, Shu-juan Zhao, Na Wang, Jia-xing Wang, Zong-fang Li, Wuding Zhou, Ke Li

Original languageEnglish
Pages (from-to)612-627
Number of pages16
JournalKidney International
Issue number3
Early online date21 Mar 2019
Accepted/In press7 Mar 2019
E-pub ahead of print21 Mar 2019
Published1 Sep 2019

King's Authors


Both the C3a/C3aR and C5a/C5aR1 axes are regarded as important pathways for inducing and regulating inflammatory responses. It is well documented that the C5a/C5aR1 axis is a potent inflammatory mediator in the pathogenesis of many clinic disorders. However, our understanding of the role of the C3a/C3aR axis in renal disorders remains limited. Contrary to the C5a/C5aR axis, we now show that the C3a/C3aR axis has a protective role in uropathogenic Escherichia coli (UPEC)–induced renal injury. C3aR-/- mice were found to develop severe renal pathology compared to wild type mice, a pathology characterized by intense tissue damage and an increased bacterial load within the kidney. This was associated with an overwhelming production of pro-inflammatory mediators and increased neutrophil infiltration in the kidney. Bone marrow chimera experiments found that tissue damage and bacterial load were significantly reduced in C3aR-/- mice that received bone marrow from wild type mice, compared with that in mice re-populated with bone marrow from C3aR-/- mice. This supports a critical role for C3aR on myeloid cells in the pathological process. Pharmacological treatment of mice with a C3aR agonist reduced both the extent of tissue injury and bacterial load. Mechanistic analyses indicated that the C3a/C3aR axis downregulates the lipopolysaccharide-induced pro-inflammatory responses in macrophages and facilitates the phagocytosis of UPEC by phagocytes. Thus, our findings clearly demonstrate a protective role of the C3a/C3aR axis in UPEC-induced renal injury, conferred by the suppression of pro-inflammatory responses and enhanced phagocytosis by macrophages.

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