Journal
MUCOSAL IMMUNOLOGY
Volume 13, Issue 1, Pages 22-33Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41385-019-0225-6
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Funding
- National Natural Science Foundation of China (NSFC) [31970133, 31670071, 81672740, 31700143]
- Intergovernmental international innovation cooperation [2018YFE0102000]
- Tianjin Science and Technology Commissioner Project [18JCZDJC36000]
- Science & Technology Development Fund of Tianjin Education Commission for Higher Education [2017ZD12]
- science foundation of Tianjin Medical University [2016KY2M08]
- National Key Technologies RD Program
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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.
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