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.

中文翻译：

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尿道致病性大肠杆菌的α-溶血素诱导 GM-CSF 介导的急性肾损伤。

尿路致病性大肠杆菌 (UPEC) 是尿路感染 (UTI) 的主要原因，可诱发急性肾盂肾炎，并可能导致永久性肾瘢痕形成和衰竭。α-溶血素 (HlyA) 是 UPEC 的一种关键毒素，会导致严重的组织损伤；然而，HlyA 诱导肾损伤的机制仍不清楚。在本研究中，肾上皮细胞分泌的粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 在体外和体内被 HlyA 上调，从而诱导 M1 巨噬细胞在肾脏中积累，并且发现 ADAM10 参与 HlyA 诱导的 GM -脑脊液。巨噬细胞消除或 GM-CSF 中和保护小鼠免受急性肾损伤，并且在 hlyA 阳性 UPEC 感染患者的尿液中检测到 GM-CSF 增加。此外，发现 HlyA 在体外通过与 Nectin-2 相互作用促进 UPEC 侵入肾上皮细胞。然而，HlyA 不影响急性肾脏感染期间的细菌滴度，并且 HlyA 诱导的侵袭对体外 GM-CSF 上调没有贡献，这表明 HlyA 诱导的 GM-CSF 与细菌侵袭无关。GM-CSF 在 HlyA 介导的肾损伤中的作用可能会导致治疗急性肾盂肾炎的新策略。