Mast cells disrupt epithelial barrier function during enteric nematode infection.
We have investigated the influence of mast cells on the barrier function of intestinal epithelium during nematode infection. Trichinella spiralis infection induces a strong type 2 cytokine-mediated inflammation, resulting in a critical mucosal mastocytosis that is known to mediate expulsion of the parasites from the intestine. The host response to infection is also characterized by an increase in mucosal leakiness. We show here that intestinal epithelial permeability is markedly elevated during infection, with kinetics that mirror the adaptive immune response to primary and secondary infection. Furthermore, we have identified degradation of the tight junction protein, occludin, thereby providing a mechanism for increased paracellular permeability during helminth infection. We further demonstrate by using anti-c-kit antibody and IL-9 transgenic mice that mast cells are directly responsible for increasing epithelial paracellular permeability and that mice deficient in a mast cell-specific protease fail to increase intestinal permeability and fail to expel their parasite burden. These results provide the mechanism whereby mucosal mast cells mediate parasite expulsion from the intestine.
McDermott
Jacqueline R
JR
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom. jacqueline.r.mcdermott@man.ac.uk
Bartram
Ruth E
RE
Knight
Pamela A
PA
Miller
Hugh R P
HR
Garrod
David R
DR
Grencis
Richard K
RK
D000818:Animals; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000235:genetics; D004847:Epithelial Cells / Q000469:parasitology; D004848:Epithelium / Q000378:metabolism / Q000469:parasitology* / Q000502:physiology; D007074:Immunoglobulin G / Q000378:metabolism; D007249:Inflammation; D016906:Interleukin-9 / Q000235:genetics; D007422:Intestines / Q000469:parasitology*; D007583:Jejunum / Q000469:parasitology; D008407:Mast Cells / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000378:metabolism; D062793:Occludin; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology; D013997:Time Factors; D017160:Trichinella spiralis / Q000472:pathogenicity*
D018932:Chemokine CCL2; D007074:Immunoglobulin G; D016906:Interleukin-9; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D019009:Proto-Oncogene Proteins c-kit