IL-9– and mast cell–mediated intestinal permeability predisposes to oral antigen hypersensitivity

Abstract

Previous mouse and clinical studies demonstrate a link between Th2 intestinal inflammation and induction of the effector phase of food allergy. However, the mechanism by which sensitization and mast cell responses occurs is largely unknown. We demonstrate that interleukin (IL)-9 has an important role in this process. IL-9–deficient mice fail to develop experimental oral antigen–induced intestinal anaphylaxis, and intestinal IL-9 overexpression induces an intestinal anaphylaxis phenotype (intestinal mastocytosis, intestinal permeability, and intravascular leakage). In addition, intestinal IL-9 overexpression predisposes to oral antigen sensitization, which requires mast cells and increased intestinal permeability. These observations demonstrate a central role for IL-9 and mast cells in experimental intestinal permeability in oral antigen sensitization and suggest that IL-9–mediated mast cell responses have an important role in food allergy.

Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism

“…In contrast to other species, including humans, where mast cells comprise 2-3% of total lamina propria cells, mast cells in the murine small intestine are infrequent, with approximately five mast cells per villus localized within the lamina propria (18,21,28). Despite this, mast cell-derived chymase impacts intestinal TJ protein expression, epithelial migration and barrier function.…”

“…Furthermore, these studies reveal a link between mast cell/chymase-mediated epithelial migration and the regulation of homeostatic intestinal barrier function. Previous studies have examined the role of mast cells in intestinal barrier function during oral antigen-or helminthinduced intestinal inflammation (17)(18)(19)(20). Repeated oral administration of ovalbumin to ovalbumin-immunized mice induced an IgE/Fc RI/mast cell-dependent increase in intestinal epithelial permeability and secretory diarrhea (18,19).…”

“…Previous studies have examined the role of mast cells in intestinal barrier function during oral antigen-or helminthinduced intestinal inflammation (17)(18)(19)(20). Repeated oral administration of ovalbumin to ovalbumin-immunized mice induced an IgE/Fc RI/mast cell-dependent increase in intestinal epithelial permeability and secretory diarrhea (18,19). Furthermore, T. spiralis infection induced intestinal mastocytosis and intestinal permeability through a protease-dependent process (17).…”

Immunity to gastrointestinal nematode infections

“…As with the role of IL-5 in promoting eosinophil responses, IL-9 acts mainly as a maturation factor for mucosal mast cells, [90][91][92] and is largely T cell derived, [93][94][95] although it can be secreted by ILC2, 96 as well as by mast cells themselves 97,98 that in turn promote enhanced secretion of IL-25, IL-33, and TSLP from epithelial cells. 99 As a result, T. muris and H. polygyrus expulsion are impaired in mast cell-deficient mice 99,100 as well as upon administration of neutralizing IL-9 antibodies, 101,102 although it should be noted that studies using mast celldeficient mice (c-kit mutants) suffer from possible confounding factors given the role for c-kit on many other cell types, and thus remain to be clarified.…”

Les lymphocytes Th9

“…En effet, l'IL-9 stimule la production du mucus, l'infiltration de leucocytes et la production d'IgE par les lymphocytes B [20]. Elle active également la production d'histamine par les mastocytes [21] leur conférant un rôle dans l'allergie chronique. À noter que la neutralisation de l'IL-9 diminue l'inflammation [22] et que, dans les lavages broncho-alvéolaires des patients allergiques, la concentration d'IL-10 est inversement corrélée à la sévérité de la maladie [23] (Tableau I).…”