Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-deficient mice.
Interleukin 4 receptor alpha (IL-4Ralpha) is essential for effective clearance of gastrointestinal nematode infections. Smooth muscle cells are considered to play a role in the type 2 immune response-driven expulsion of gastrointestinal nematodes. Previous studies have shown in vitro that signal transducer and activator of transcription 6 signaling in response to parasitic nematode infection significantly increases smooth muscle cell contractility. Inhibition of the IL-4Ralpha pathway inhibits this response. How this response manifests itself in vivo is unknown. In this study, smooth muscle cell IL-4Ralpha-deficient mice (SM-MHC(Cre)IL-4Ralpha(-/lox)) were generated and characterized to uncover any role for IL-4/IL-13 in this non-immune cell type in response to Nippostrongylus brasiliensis infection. IL-4Ralpha was absent from alpha-actin-positive smooth muscle cells, while other cell types showed normal IL-4Ralpha expression, thus demonstrating efficient cell-type-specific deletion of the IL-4Ralpha gene. N. brasiliensis-infected SM-MHC(Cre)IL-4Ralpha(-/lox) mice showed delayed ability to resolve infection with significantly prolonged fecal egg recovery and delayed worm expulsion. The delayed expulsion was related to a delayed intestinal goblet cell hyperplasia, reduced T helper 2 cytokine production in the mesenteric lymph node, and reduced M3 muscarinic receptor expression during infection. Together, these results demonstrate that in vivo IL-4Ralpha-responsive smooth muscle cells are beneficial for N. brasiliensis expulsion by coordinating T helper 2 cytokine responses, goblet hyperplasia, and acetylcholine responsiveness, which drive smooth muscle cell contractions.
Horsnell
William G C
WG
Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Cutler
Antony J
AJ
Hoving
J Claire
JC
Hoving
Claire J
CJ
Mearns
Helen
H
Myburgh
Elmarie
E
Arendse
Berenice
B
Finkelman
Fred D
FD
Owens
Gary K
GK
Erle
Dave
D
Brombacher
Frank
F
D000818:Animals; D015870:Gene Expression; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D053662:Interleukin-4 Receptor alpha Subunit / Q000378:metabolism*; D051379:Mice; D009130:Muscle, Smooth / Q000378:metabolism*; D009349:Nematode Infections / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000096:biosynthesis / Q000378:metabolism*
D053662:Interleukin-4 Receptor alpha Subunit; D011950:Receptors, Cholinergic