Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

Abstract

AbstractIL-4 is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection withSchistosoma haematobiumworms, remains poorly understood due to a historical lack of animal models. The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis by injecting the bladder walls of IL-4 receptor-alpha knockout(Il4ra−/−) and wild type mice withS. haematobiumeggs. Readouts included bladder histology andex vivoassessments of urothelial proliferation, cell cycle and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial cell proliferationin vitro, including cell cycle status and phosphorylation patterns of major downstream regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of granulomatous responses to bladder-wall injectedS. haematobiumeggs inIl4ra−/−versus wild type mice.S. haematobiumegg injection triggered significant urothelial proliferation, including evidence of urothelial hyperdiploidy and cell cycle skewing in wild type but notIl4ra−/−mice. Urothelial exposure to IL-4in vitroled to cell cycle polarization and increased phosphorylation of AKT. Our results show IL-4 signaling is required for key pathogenic features of urogenital schistosomiasis, and that particular aspects of this signaling pathway may exert these effects directly on the urothelium. These findings point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis.