ILC2-derived CGRP triggers acute inflammation and nociceptive responses in bacterial cystitis

Calcitonin gene-related peptide (CGRP), a neuropeptide involved in nociceptor neuronal function, plays a critical role in mediating neuroinflammation and pain. In this study, we find that bladder group 2 innate lymphoid cells (ILC2s) function as primary producers of CGRP in the early phase of bacterial cystitis, contributing to increased inflammation, altered voiding behavior, and heightened pelvic allodynia. Furthermore, we demonstrate that interleukin (IL)-33, a cytokine secreted by urothelial cells, upregulates CGRP production by ILC2s in the bladder during uropathogenic Escherichia coli (UPEC) infection. Moreover, our research reveals that monocytes expressing high levels of receptor activity-modifying protein 1 (RAMP1), a CGRP receptor, mediate the pro-inflammatory effects of CGRP-producing ILC2s. In summary, our results underscore the significance of the immune cell-derived neuropeptides in the pathology of UPEC infection, suggesting a promising therapeutic approach targeting the IL-33-ILC2-CGRP axis for managing lower urinary tract symptoms in bacterial cystitis.