The C3a/C3aR axis mediates anti-inflammatory activity and protects against uropathogenic E coli-induced kidney injury in mice
The C3a/C3aR axis mediates anti-inflammatory activity and protects against uropathogenic E coli-induced kidney injury in mice
复制标题
C3a/C3aR 轴介导抗炎活性并防止小鼠泌尿道致病性大肠杆菌诱导的肾损伤
DOI：
10.1016/j.kint.2019.03.005
复制
发表时间：
2019
影响因子：
19.6
通讯作者：
Li Ke
中科院分区：
文献类型：
--
作者：
Wu Kun Yi;Zhang Ting;Zhao Guo Xiu;Ma Ning;Zhao Shu Juan;Wang Na;Wang Jia Xing;Li Zong Fang;Zhou Wuding;Li Ke
C3 a/C3 aR和C5 a/C5 aR 1轴被认为是诱导和调节炎症反应的重要途径。C5 a/C5 aR 1轴在许多临床疾病的发病机制中是一种有效的炎症介质。然而，我们对C3 a/C3 aR轴在肾脏疾病中的作用的理解仍然有限。与C5 a/C5 aR轴相反，我们发现C3 a/C3 aR轴在致尿路感染大肠杆菌（UPEC）诱导的肾损伤中具有保护作用。与野生型小鼠相比，C3 aR-/-小鼠出现严重的肾脏病理，病理特征为严重的组织损伤和肾脏内细菌负荷增加。这与促炎介质的大量产生和肾脏中性粒细胞浸润增加有关。骨髓嵌合体实验发现，与用来自C3 aR-/-小鼠的骨髓重新填充的小鼠相比，接受来自野生型小鼠的骨髓的C3 aR-/-小鼠的组织损伤和细菌负荷显著降低。这支持了C3 aR在病理过程中对骨髓细胞的关键作用。用C3 aR激动剂对小鼠进行药物治疗，可降低组织损伤程度和细菌负荷。机制分析表明，C3 a/C3 aR轴下调巨噬细胞中脂多糖诱导的促炎反应，并促进吞噬细胞对UPEC的吞噬。因此，我们的研究结果清楚地证明了C3 a/C3 aR轴在UPEC诱导的肾损伤中的保护作用，这是通过抑制促炎反应和增强巨噬细胞的吞噬作用来实现的。
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 inC3aR-/-mice that received bone marrow from wild type mice, compared with that in mice re-populated with bone marrow fromC3aR-/-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.