IL-4R{alpha}-responsive smooth muscle cells increase intestinal hypercontractility and contribute to resistance during acute Schistosomiasis.
Interleukin-(IL)-4 and IL-13 signal through heterodimeric receptors containing a common IL-4 receptor-alpha (IL-4Ralpha) subunit, which is important for protection against helminth infections, including schistosomiasis. Previous studies demonstrated important roles for IL-4Ralpha-responsive hematopoietic cells, including T cells and macrophages in schistosomiasis. In this study, we examined the role of IL-4Ralpha responsiveness by nonhematopoietic smooth muscle cells during experimental acute murine schistosomiasis. Comparative Schistosoma mansoni infection studies with smooth muscle cell-specific IL-4Ralpha-deficient (SM-MHC(cre)IL-4Ralpha(-/flox)) mice, heterozygous control (IL-4Ralpha(-/flox)) mice, and global IL-4Ralpha-deficient (IL-4Ralpha(-/-)) mice were conducted. S. mansoni-infected SM-MHC(cre)IL-4Ralpha(-/flox) mice showed increased weight loss and earlier mortalities compared with IL-4Ralpha(-/flox) mice, despite comparable T(H)2/type 2 immune responses. In contrast to highly susceptible IL-4Ralpha-deficient mice, increased susceptibility in SM-MHC(cre)IL-4Ralpha(-/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-4Ralpha 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.
Marillier
Reece G
RG
International Centre for Genetic Engineering and Biotechnology (ICGEB Univ. of Cape Town Campus, Wernher Beit South, 7925 Cape Town, South Africa.
Brombacher
Tiroyaone M
TM
Dewals
Benjamin
B
Leeto
Mosiuoa
M
Barkhuizen
Mark
M
Govender
Dhirendra
D
Kellaway
Lauriston
L
Horsnell
William G C
WG
Brombacher
Frank
F
D000818:Animals; D005769:Gastrointestinal Motility / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D007422:Intestines / Q000473:pathology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D053662:Interleukin-4 Receptor alpha Subunit
D018793:Interleukin-13; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit