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The C3a/C3aR axis mediates anti-inflammatory activity and protects against uropathogenic E coli-induced kidney injury in mice.
Kidney International ( IF 14.8 ) Pub Date : 2019-03-21 , DOI: 10.1016/j.kint.2019.03.005 Kun-Yi Wu 1 , Ting Zhang 1 , Guo-Xiu Zhao 1 , Ning Ma 1 , Shu-Juan Zhao 1 , Na Wang 1 , Jia-Xing Wang 1 , Zong-Fang Li 2 , Wuding Zhou 3 , Ke Li 4
Kidney International ( IF 14.8 ) Pub Date : 2019-03-21 , DOI: 10.1016/j.kint.2019.03.005 Kun-Yi Wu 1 , Ting Zhang 1 , Guo-Xiu Zhao 1 , Ning Ma 1 , Shu-Juan Zhao 1 , Na Wang 1 , Jia-Xing Wang 1 , Zong-Fang Li 2 , Wuding Zhou 3 , Ke Li 4
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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.
中文翻译：
C3a/C3aR 轴介导抗炎活性并保护小鼠免受尿路致病性大肠杆菌引起的肾损伤。
C3a/C3aR 和 C5a/C5aR1 轴都被认为是诱导和调节炎症反应的重要途径。有充分证据表明，C5a/C5aR1 轴是许多临床疾病发病机制中的有效炎症介质。然而，我们对 C3a/C3aR 轴在肾脏疾病中的作用的理解仍然有限。与 C5a/C5aR 轴相反，我们现在表明 C3a/C3aR 轴在尿路致病性大肠杆菌 (UPEC) 诱导的肾损伤中具有保护作用。与野生型小鼠相比，C3aR-/- 小鼠被发现出现严重的肾脏病变，这种病变的特点是严重的组织损伤和肾脏内细菌负荷的增加。这与大量促炎介质的产生和肾脏中的中性粒细胞浸润增加有关。骨髓嵌合体实验发现，与重新植入 C3aR-/- 小鼠骨髓的小鼠相比，接受野生型小鼠骨髓的 C3aR-/- 小鼠的组织损伤和细菌负荷显着降低。这支持了 C3aR 在病理过程中对骨髓细胞的关键作用。用 C3aR 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，C3a/C3aR 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 的吞噬作用。因此，我们的研究结果清楚地证明了 C3a/C3aR 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而赋予的。
更新日期：2019-05-16
中文翻译：
C3a/C3aR 轴介导抗炎活性并保护小鼠免受尿路致病性大肠杆菌引起的肾损伤。
C3a/C3aR 和 C5a/C5aR1 轴都被认为是诱导和调节炎症反应的重要途径。有充分证据表明，C5a/C5aR1 轴是许多临床疾病发病机制中的有效炎症介质。然而，我们对 C3a/C3aR 轴在肾脏疾病中的作用的理解仍然有限。与 C5a/C5aR 轴相反，我们现在表明 C3a/C3aR 轴在尿路致病性大肠杆菌 (UPEC) 诱导的肾损伤中具有保护作用。与野生型小鼠相比，C3aR-/- 小鼠被发现出现严重的肾脏病变，这种病变的特点是严重的组织损伤和肾脏内细菌负荷的增加。这与大量促炎介质的产生和肾脏中的中性粒细胞浸润增加有关。骨髓嵌合体实验发现，与重新植入 C3aR-/- 小鼠骨髓的小鼠相比，接受野生型小鼠骨髓的 C3aR-/- 小鼠的组织损伤和细菌负荷显着降低。这支持了 C3aR 在病理过程中对骨髓细胞的关键作用。用 C3aR 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，C3a/C3aR 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 的吞噬作用。因此，我们的研究结果清楚地证明了 C3a/C3aR 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而赋予的。
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