Single-cell analysis reveals an important role of CD137L+ macrophages in the host response to uropathogenic Escherichia coli infection in the bladder

Uropathogenic Escherichia coli (UPEC) typically trigger rapid and robust innate immune responses in the bladder. In order to identify the key facets of the host response that influence pathogen clearance and tissue damage, single-cell RNA sequencing was used to investigate the transcriptomic changes of immune cells in mouse bladder after UPEC infection. Single-cell analysis revealed significant elevated CD137L expression in macrophages and dendritic cells in bladder after UPEC infection. CD137L defines a macrophage population in bladder that is important for the host response to UPEC infection. Deletion of CD137L in macrophages resulted in severe bacterial burden and bladder inflammation during the acute stage of UPEC infection. Further study demonstrated that the crucial role of CD137L+ macrophages in protecting against UPEC infection might be mediated by Tregs, which express high levels of CD137 (the receptor for CD137L). Deletion of CD137L+ macrophages decreased Treg cells and led to a reduction in inhibitory factors such as CTLA-4 and PD-1 on Tregs. Deletion of Tregs using Foxp3DTR mice also aggravated inflammatory reactions, bacterial load, and urothelial destruction during the acute phase of UPEC infection. Similarly, the deletion of CD137 in Tregs resulted in a decrease in these inhibitory factors on Tregs, causing more severe bladder inflammation during UPEC infection. These results illuminate the immune landscape of the bladder infected by UPEC and highlight the crucial role of CD137L+ macrophages during UPEC infection in bladder. CD137L+ macrophages might prevent excessive inflammatory response during the host response to UPEC infection by regulating Tregs.