Host regulation of liver fibroproliferative pathology during experimental schistosomiasis via interleukin-4 receptor alpha.

ABSTRACT: Interleukin-4 receptor (IL-4R?) is critical for the initiation of type-2 immune responses and implicated in the pathogenesis of experimental schistosomiasis. IL-4R? mediated type-2 responses are critical for the control of pathology during acute schistosomiasis. However, type-2 responses tightly associate with fibrogranulomatous inflammation that drives host pathology during chronic schistosomiasis. To address such controversy on the role of IL-4R?, we generated a novel inducible IL-4R?-deficient mouse model that allows for temporal knockdown of il-4r? gene after oral administration of Tamoxifen. Interrupting IL-4R? mediated signaling during the acute phase impaired the development of protective type-2 immune responses, leading to rapid weight loss and premature death, confirming a protective role of IL-4R? during acute schistosomiasis. Conversely, IL-4R? removal at the chronic phase of schistosomiasis ameliorated the pathological fibro-granulomatous pathology and reversed liver scarification without affecting the host fitness. This amelioration of the morbidity was accompanied by a reduced Th2 response and increased frequencies of FoxP3+ Tregs and CD1dhiCD5+ Bregs. Collectively, these data demonstrate that IL-4R? mediated signaling has two opposing functions during experimental schistosomiasis depending on the stage of advancement of the disease and indicate that interrupting IL-4R? mediated signaling is a viable therapeutic strategy to ameliorate liver fibroproliferative pathology in diseases like chronic schistosomiasis.

SUBMITTER: Nono JK 

PROVIDER: S-EPMC5578697 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature