Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-deficient mice

William G C Horsnell; Antony J Cutler; Claire J Hoving; Helen Mearns; Elmarie Myburgh; Berenice Arendse; Fred D Finkelman; Gary K Owens; Dave Erle; Frank Brombacher

doi:10.1371/journal.ppat.0030001

Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-deficient mice

William G C Horsnell, Antony J Cutler, Claire J Hoving, Helen Mearns, Elmarie Myburgh, Berenice Arendse, Fred D Finkelman, Gary K Owens, Dave Erle, Frank Brombacher

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	e1
Journal	PLOS PATHOGENS
Volume	3
Issue number	1
DOIs	https://doi.org/10.1371/journal.ppat.0030001
Publication status	Published - Jan 2007

Keywords

Animals
Gene Expression
Goblet Cells/metabolism
Hyperplasia
Interleukin-4 Receptor alpha Subunit/metabolism
Mice
Muscle, Smooth/metabolism
Nematode Infections/immunology
Receptors, Cholinergic/biosynthesis

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10.1371/journal.ppat.0030001

Cite this

@article{fd16bcc84b5e4d33aa07555b40f1c4b9,

title = "Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-deficient mice",

abstract = "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.",

keywords = "Animals, Gene Expression, Goblet Cells/metabolism, Hyperplasia, Interleukin-4 Receptor alpha Subunit/metabolism, Mice, Muscle, Smooth/metabolism, Nematode Infections/immunology, Receptors, Cholinergic/biosynthesis",

author = "Horsnell, {William G C} and Cutler, {Antony J} and Hoving, {Claire J} and Helen Mearns and Elmarie Myburgh and Berenice Arendse and Finkelman, {Fred D} and Owens, {Gary K} and Dave Erle and Frank Brombacher",

year = "2007",

month = jan,

doi = "10.1371/journal.ppat.0030001",

language = "English",

volume = "3",

pages = "e1",

journal = "PLOS PATHOGENS",

issn = "1553-7366",

publisher = "Public Library of Science",

number = "1",

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TY - JOUR

T1 - Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-deficient mice

AU - Horsnell, William G C

AU - Cutler, Antony J

AU - Hoving, Claire J

AU - Mearns, Helen

AU - Myburgh, Elmarie

AU - Arendse, Berenice

AU - Finkelman, Fred D

AU - Owens, Gary K

AU - Erle, Dave

AU - Brombacher, Frank

PY - 2007/1

Y1 - 2007/1

N2 - 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.

AB - 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.

KW - Animals

KW - Gene Expression

KW - Goblet Cells/metabolism

KW - Hyperplasia

KW - Interleukin-4 Receptor alpha Subunit/metabolism

KW - Mice

KW - Muscle, Smooth/metabolism

KW - Nematode Infections/immunology

KW - Receptors, Cholinergic/biosynthesis

U2 - 10.1371/journal.ppat.0030001

DO - 10.1371/journal.ppat.0030001

M3 - Article

C2 - 17222057

SN - 1553-7366

VL - 3

SP - e1

JO - PLOS PATHOGENS

JF - PLOS PATHOGENS

IS - 1

ER -