Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism.
Altered intestinal barrier function is postulated to be a central predisposing factor to intestinal diseases, including inflammatory bowel diseases and food allergies. However, the mechanisms involved in maintaining homeostatic intestinal barrier integrity remain undefined. In this study, we demonstrate that mice deficient in mast cells (Kit(W-sh/W-sh) [Wsh]) or mast cell chymase (Mcpt4(-/-)) have significantly decreased basal small intestinal permeability compared with wild-type (WT) mice. Altered intestinal barrier function was linked to decreased intestinal epithelial cell migration along the villus/crypt axis, altered intestinal morphology, and dysregulated claudin-3 crypt expression. Remarkably, engraftment of Wsh mice with WT but not Mcpt4(-/-) mast cells restored intestinal epithelial cell migration, morphology, and intestinal epithelial barrier function. Collectively, these findings identify a mechanism by which mast cells regulate homeostatic intestinal epithelial migration and barrier function.
Groschwitz
Katherine R
KR
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Ahrens
Richard
R
Osterfeld
Heather
H
Gurish
Michael F
MF
Han
Xiaonan
X
Abrink
Magnus
M
Finkelman
Fred D
FD
Pejler
Gunnar
G
Hogan
Simon P
SP
D000818:Animals; D018938:Caco-2 Cells; D002465:Cell Movement / Q000502:physiology; D053818:Chymases / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D062465:Claudin-3; D004848:Epithelium / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000166:cytology / Q000502:physiology*; D007583:Jejunum / Q000166:cytology / Q000502:physiology; D008407:Mast Cells / Q000502:physiology* / Q000637:transplantation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010539:Permeability / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C568122:CLDN3 protein, human; D062465:Claudin-3; C568123:Cldn3 protein, mouse; D008565:Membrane Proteins; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; C066932:mast cell protease 4; D053818:Chymases