Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
Department of Clinical Laboratory, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China.
Mucosal Immunol. 2020 Jan;13(1):22-33. doi: 10.1038/s41385-019-0225-6. Epub 2019 Nov 12.
Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs), inducing acute pyelonephritis and may result in permanent renal scarring and failure. Alpha-hemolysin (HlyA), a key UPEC toxin, causes serious tissue damage; however, the mechanism through which HlyA induces kidney injury remains unclear. In the present study, granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by renal epithelial cells was upregulated by HlyA in vitro and in vivo, which induced M1 macrophage accumulation in kidney, and ADAM10 was found involved in HlyA-induced GM-CSF. Macrophage elimination or GM-CSF neutralization protected against acute kidney injury in mice, and increased GM-CSF was detected in urine of patients infected by hlyA-positive UPEC. In addition, HlyA was found to promote UPEC invasion into renal epithelial cells by interacting with Nectin-2 in vitro. However, HlyA did not affect bacterial titers during acute kidney infections, and HlyA-induced invasion did not contribute to GM-CSF upregulation in vitro, which indicate that HlyA-induced GM-CSF is independent of bacteria invasion. The role of GM-CSF in HlyA-mediated kidney injury may lead to novel strategies to treat acute pyelonephritis.
尿路致病性大肠杆菌（UPEC）是尿路感染（UTIs）的主要原因，可引起急性肾盂肾炎，并可能导致永久性肾瘢痕和衰竭。α-溶血素（HlyA）是一种关键的 UPEC 毒素，可导致严重的组织损伤；然而，HlyA 诱导肾脏损伤的机制尚不清楚。在本研究中，HlyA 在体外和体内均可上调肾脏上皮细胞分泌的粒细胞-巨噬细胞集落刺激因子（GM-CSF），诱导肾脏中 M1 巨噬细胞聚集，并且发现 ADAM10 参与 HlyA 诱导的 GM-CSF。巨噬细胞消除或 GM-CSF 中和可防止小鼠急性肾损伤，并且在感染 hlyA 阳性 UPEC 的患者的尿液中检测到 GM-CSF 增加。此外，HlyA 被发现可通过体外与 Nectin-2 相互作用促进 UPEC 侵入肾脏上皮细胞。然而，HlyA 不会影响急性肾脏感染期间的细菌滴度，并且 HlyA 诱导的入侵在体外对 GM-CSF 的上调没有贡献，这表明 HlyA 诱导的 GM-CSF 独立于细菌入侵。GM-CSF 在 HlyA 介导的肾脏损伤中的作用可能为治疗急性肾盂肾炎提供新的策略。
