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

Justin Komguep Nono; Hlumani Ndlovu; Nada Abdel Aziz; Thabo Mpotje; Lerato Hlaka; Frank Brombacher

doi:10.1371/journal.pntd.0005861

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

PLoS Negl Trop Dis. 2017 Aug 21;11(8):e0005861. doi: 10.1371/journal.pntd.0005861. eCollection 2017 Aug.

Authors

Justin Komguep Nono^{1

2

3}, Hlumani Ndlovu^{1

2

4}, Nada Abdel Aziz^{1

2

5}, Thabo Mpotje^{1

2}, Lerato Hlaka^{1

2}, Frank Brombacher^{1

2}

Affiliations

¹ Cytokines and Diseases Group, International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa.
² Division of Immunology, Health Science Faculty, University of Cape Town & Immunology of Infectious Disease Research Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa.
³ The Medical Research Centre, Institute of Medical Research and Medicinal Plant Studies (IMPM), Ministry of Scientific Research and Innovation, Yaoundé, Cameroon.
⁴ Department of Integrative Biomedical Sciences, Health Sciences Faculty, University of Cape Town, Cape Town, South Africa.
⁵ Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.

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.

MeSH terms

Acute Disease
Animals
Disease Models, Animal
Female
Fibrosis
Host-Parasite Interactions*
Liver / pathology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, Cell Surface / genetics
Receptors, Cell Surface / immunology*
Schistosomiasis / genetics
Schistosomiasis / immunology*
Th2 Cells / immunology*

Substances

Il4ra protein, mouse
Receptors, Cell Surface

Grants and funding

This work was supported by the International Centre for Genetic Engineering & Biotechnology (ICGEB), Cape Town. Further support was provided through the South African Medical Research Council (SAMRC) Unit on Immunology of Infectious Diseases (FB) and the South African Research Chair initiative (SARChi) to FB. JKN received a Sydney Brenner postdoctoral Fellowship from the Academy of Science of South Africa. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.