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

Abstract

Interleukin-4 receptor (IL-4Rα) is critical for the initiation of type-2 immune responses and implicated in the pathogenesis of experimental schistosomiasis. IL-4Rα 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-4Rα, we generated a novel inducible IL-4Rα-deficient mouse model that allows for temporal knockdown of il-4rα gene after oral administration of Tamoxifen. Interrupting IL-4Rα 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-4Rα during acute schistosomiasis. Conversely, IL-4Rα 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-4Rα mediated signaling has two opposing functions during experimental schistosomiasis depending on the stage of advancement of the disease and indicate that interrupting IL-4Rα mediated signaling is a viable therapeutic strategy to ameliorate liver fibroproliferative pathology in diseases like chronic schistosomiasis.

IL-4Rα-expressing CD11c+ cells contribute to driving optimal cellular responses during Schistosoma mansoni infection in mice

“…This further supports the central role of Th2 cytokines and IL‐4Ra mediated signaling in regulating liver fibrogranulomatous inflammation during schistosomiasis. This aligns with our recent study, which showed that temporal interference with IL‐4Rα expression by oral administration of tamoxifen in i Cre‐/+ IL‐4Rα −/lox mice during experimental schistosomiasis reduces perioval granulomatous inflammation, tissue fibrosis, scarring, and hepatosplenomegaly . Our observation of a reduced granulomatous inflammation in CD11c cre IL‐4Rα −/lox mice therefore suggests that IL‐4Rα‐expressing CD11c + cells may be contributing to the fibrogranulomatous tissue inflammation in S. mansoni ‐infected mice.…”

“…As expected, infected CD11c cre IL‐4Rα −/lox mice had reduced tissue granulomatous pathology indicated by reduced granuloma size and fibrosis compared to littermate control mice, in line with the observed impaired Th2 immunity. It is an established fact in the literature that Th2 cytokines, particularly IL‐4 and IL‐13, are critical for liver granuloma formation . Moreover, IL‐13 has been shown to be a master cytokine mediating fibrogenesis in tandem with other type 2 cytokines during schistosomiasis .…”

Batf2 differentially regulates tissue immunopathology in Type 1 and Type 2 diseases

“…4f) remained similar between WT and Batf2 −/− mice. As either liver and/or small intestinal pathology usually drive host susceptibility to schistosomiasis morbidity, 16,17 we further investigated for indications of liver or small intestinal pathology in these mice, as we reasoned that differential pathology in the absence of differential parasite burden might explain the susceptibility of Batf2 −/− mice during acute schistosomiasis. Batf2 deficiency did not prompt any major aggravation of the liver pathology as determined by the measure of hepatomegaly ( Fig.…”

T Lymphocyte-Mediated Liver Immunopathology of Schistosomiasis

“…For instance, IL-4-deficient mice that cannot mount a normal Th2 response develop an unchecked Th1 response and die earlier than immunity intact mice when infected by S. mansoni (6). Similarly, in a Tamoxifen-induced IL-4 receptor α (IL-4Rα)-deficient mouse model, interrupting IL-4Rα-mediated signaling during the acute stage decreased protective Th2 responses, leading to severe disease and premature death (17). Therefore, moderate Th1 responses are involved in the acute schistosomiasis and early granuloma formation, whereas excessive polarization toward the Th1 response is detrimental to the host.…”