IL-4Rα-responsive smooth muscle cells increase intestinal hypercontractility and contribute to resistance during acute Schistosomiasis

Author:

Marillier Reece G.1,Brombacher Tiroyaone M.1,Dewals Benjamin1,Leeto Mosiuoa1,Barkhuizen Mark1,Govender Dhirendra2,Kellaway Lauriston3,Horsnell William G. C.1,Brombacher Frank1

Affiliation:

1. International Centre for Genetic Engineering and Biotechnology and Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty;

2. Department of Clinical Laboratory Sciences Anatomical, Division of Pathology, Health Sciences Faculty; and

3. Department of Anatomy and Physiology, Health Sciences Faculty, University of Cape Town, Cape Town, South Africa

Abstract

Interleukin-(IL)-4 and IL-13 signal through heterodimeric receptors containing a common IL-4 receptor-α (IL-4Rα) subunit, which is important for protection against helminth infections, including schistosomiasis. Previous studies demonstrated important roles for IL-4Rα-responsive hematopoietic cells, including T cells and macrophages in schistosomiasis. In this study, we examined the role of IL-4Rα responsiveness by nonhematopoietic smooth muscle cells during experimental acute murine schistosomiasis. Comparative Schistosoma mansoni infection studies with smooth muscle cell-specific IL-4Rα-deficient (SM-MHCcreIL-4Rα−/flox) mice, heterozygous control (IL-4Rα−/flox) mice, and global IL-4Rα-deficient (IL-4Rα−/−) mice were conducted. S. mansoni -infected SM-MHCcreIL-4Rα−/flox mice showed increased weight loss and earlier mortalities compared with IL-4Rα−/flox mice, despite comparable TH2/type 2 immune responses. In contrast to highly susceptible IL-4Rα-deficient mice, increased susceptibility in SM-MHCcreIL-4Rα−/flox mice was not accompanied by intestinal tissue damage and subsequent sepsis. However, both susceptible mutant mouse strains failed to efficiently expel eggs, demonstrated by egg reduction in the feces compared with control mice. Reduced egg expulsion was accompanied by impaired IL-4/IL-13-mediated hypercontractile intestinal responses, which was present in the more resistant control mice. Together, we conclude that IL-4Rα responsiveness by smooth muscle cells and subsequent IL-4- and IL-13-mediated hypercontractility are required for host protection during acute schistosomiasis to efficiently expel S. mansoni eggs and to prevent premature mortality.

Publisher

American Physiological Society

Subject

Physiology (medical),Gastroenterology,Hepatology,Physiology

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