Group 3 Innate Lymphoid Cells Protect the Host from the Uropathogenic Escherichia coli Infection in the Bladder

Abstract

Innate lymphoid cells (ILCs) are crucial in orchestrating immunity and maintaining tissue homeostasis in various barrier tissues, but whether ILCs influence immune responses in the urinary tract remains poorly understood. Here, bladder‐resident ILCs are comprehensively explored and identified their unique phenotypic and developmental characteristics. Notably, bladder‐resident ILCs rapidly respond to uropathogenic Escherichia coli (UPEC) infection. It is found that ILC3 is necessary for early protection against UPEC infection in the bladder. Mechanistically, UPEC infection leads to interleukin (IL)‐1β production in the bladder via a MyD88‐dependent pathway, which promotes ILC3 activation. ILC3‐expressed IL‐17A further recruits neutrophils and controls UPEC infection in the bladder. Together, these results demonstrate a critical role for bladder ILCs in the host defense against UPEC infection.

Type 2 innate lymphoid cells are not involved in mouse bladder tumor development

“…Under steady-state conditions, they also suggested that ILC2s were the main ILC subset in mouse bladders, consistent with our own results (38,44). Nevertheless, while the levels of ILC subsets differed between these studies, they consistently reported higher levels of bladder-infiltrating ILC3s at steady state compared to our results (38,44). These differences could be potentially explained by differences in the lineage and/or gating strategies.…”

“…IL-33 signaling through its receptor ST2 has been reported as a key pathway for inducing the secretion of type 2 cytokines by ILC2s, and neutralizing ST2 in vivo significantly limited ILC2 activation (35)(36)(37). We first confirmed the high expression of ST2 by bladder ILC2s compared to ILC1s and 3, which remained stable along the bladder tumor growth (Supplementary Figure 3C), consistent with previous observations (38) and suggesting that bladder ILC2s may be responsive to IL-33. Mice were then treated with an anti-ST2 blocking antibody (Figure 3D).…”

“…Scharff et al ( 43) are among the first to report bladderresident ILC populations. Together with more recent studies (38,44), they reported an increase of ILC3s in mouse bladders following uropathogenic Escherichia coli infection and highlighted their importance against the infection. Under steady-state conditions, they also suggested that ILC2s were the main ILC subset in mouse bladders, consistent with our own results (38,44).…”

“…Together with more recent studies (38,44), they reported an increase of ILC3s in mouse bladders following uropathogenic Escherichia coli infection and highlighted their importance against the infection. Under steady-state conditions, they also suggested that ILC2s were the main ILC subset in mouse bladders, consistent with our own results (38,44). Nevertheless, while the levels of ILC subsets differed between these studies, they consistently reported higher levels of bladder-infiltrating ILC3s at steady state compared to our results (38,44).…”

The impact of biological sex on diseases of the urinary tract

“…In female C57BL/6 mice infected intravesically, testosterone treatment reduces infiltration of CD4 + T cells, type 3 innate lymphoid cells (ILC3), and γδ T cells 50 , all of which are major producers of IL-17 58 . While this study identified a difference in the total number of ILCs in female mice compared to male mice, in which female mice have more bladder resident ILCs 50 , another study showed no differences in the percentages of ILC subsets among CD45+ cells in the naive urinary tract when comparing female and male mice 59 . Interestingly, female mice treated with an IL-17neutralizing antibody fail to resolve their infection 50 .…”