Multimodal Single‐Cell Analyses Outline the Immune Microenvironment and Therapeutic Effectors of Interstitial Cystitis/Bladder Pain Syndrome

Abstract Interstitial cystitis/bladder pain syndrome (IC/BPS) has a significant impact on quality of life, but the etiopathogenesis remains largely unknown. The bladder microenvironment of patients with IC/BPS to obtain biological evidence supporting diagnosis and novel therapy is systematically characterized. Single‐cell RNA sequencing (scRNA‐seq) and image mass cytometry (IMC) are applied to bladder biopsies of the IC/BPS cohort. A total of 42 distinct cell clusters are identified from different groups. The increased hyperactivated Th1‐biased response, but not Th2‐biased response, and decreased immunosuppressive Treg are elucidated in the bladder microenvironment of non‐Hunner‐type IC (NHIC)/Hunner‐type IC (HIC). M2/M2‐like macrophage extends in the HIC and M1‐like macrophage extends in NHIC, all of which secrete a range of chemokines with different pattern. The pro‐inflammatory mediators, TNF‐α, produced by tissue‐resident macrophages and IL6, by the inflammatory fibroblasts are identified as key mediators of IC/BPS pathogenesis. Additionally, a regulatory network between different cell types is observed as a shift from structural cell communication in unaffected normal bladder to a Macrophage‐Endothelial‐dominated interactome in NHIC/HIC. The results demonstrate the high heterogeneity in NHIC/HIC, and provide an essential resource for diagnosis, and treatment of IC/BPS in the future by highlighting the importance of the microenvironment of bladder mucosa.