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Mast cell-mediated intestinal barrier function in homeostasis and disease

Groschwitz, Katherine R.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291389792

Abstract Details

2010, PhD, University of Cincinnati, Medicine: Immunology.
Regulation of intestinal epithelial barrier function is critical for preventing the passage of luminal contents, while concurrently maintaining vital nutrient uptake. Disruptions in the intestinal barrier are a consequence of numerous diseases and recently have been postulated to be an important factor in the development of diseases, such as food allergies and inflammatory bowel disease. Mast cells are highly granulated immune cells involved in innate and adaptive immunity that reside in the intestine and are classically known for their effector role in allergy and inflammation. They store and when activated, for example by allergens or pathogens, secrete a variety of preformed mediators. Additionally, mast cells undergo a constitutive, low-level “piecemeal” release of selected mediators. Mast cells and their mediators, including proteases, cytokines and lipid-derived mediators, can alter intestinal barrier function during inflammation and disease. However, there is a lack of knowledge concerning regulation of the intestinal barrier under healthy, homeostatic conditions. The major objective of this dissertation was to define the role of mast cells in the regulation of intestinal epithelial barrier function, in particular, during homeostasis and in relation to food allergic reactions. We demonstrate that mice deficient in mast cells or the mast cell chymase Mcpt4 have alterations in their homeostatic intestinal barrier, including decreased intestinal permeability, decreased epithelial cell migration, altered intestinal morphology and decreased expression of the tight junction protein claudin-3. Bone marrow-derived mast cell reconstitution experiments confirmed that mast cells regulate the homeostatic intestinal barrier in a chymase/Mcpt4-dependent manner. We examined the mechanism by which chymase disrupts barrier function and show that chymase induces a biphasic change in intestinal epithelial cell barrier function. Phase I was associated with decreased expression of the tight junction protein claudin-5, followed by Phase II, which was characterized by increased protease activated receptor-2 activation and matrix metalloprotease-2 production and activation. Both phases require the chymotryptic activity of chymase, suggesting proteolytic cleavage to remove claudin-5 from the tight junction and to activate pro-matrix metalloprotease-2. In addition to regulating the intestinal barrier during homeostasis, our work defines a critical role for mast cells in altering barrier function both in the predisposition to and pathology of food allergies. Depletion or pharmacologic stabilization of mast cells demonstrates that mast cells regulate intestinal permeability in a murine model of food allergies. Transgenic intestinal overexpression of IL-9 induced an intestinal mastocytosis and mast cell-dependent increase in intestinal permeability. Notably, the mast cell-mediated increase in intestinal permeability was sufficient to facilitate oral sensitization to food antigens and the development of clinical symptoms of food allergies. Collectively, this work defines a critical homeostatic and pathogenic role for mast cells in the regulation of intestinal barrier function, dysregulation of which can lead to food antigen sensitization and the induction of food allergies.
Simon Hogan, PhD (Committee Chair)
Richard Strait, MD (Committee Member)
Marsha Wills-Karp, PhD (Committee Member)
Lee Denson, MD (Committee Member)
Fred Finkelman, MD (Committee Member)
Marc Rothenberg, MD, PhD (Committee Member)
316 p.
Immunology
Mast cell; Chymase; Intestinal permeability; Food allergy; MMP; IL-9

Recommended Citations

Citations

  • Groschwitz, K. R. (2010). Mast cell-mediated intestinal barrier function in homeostasis and disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291389792

    APA Style (7th edition)

  • Groschwitz, Katherine. Mast cell-mediated intestinal barrier function in homeostasis and disease. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291389792.

    MLA Style (8th edition)

  • Groschwitz, Katherine. "Mast cell-mediated intestinal barrier function in homeostasis and disease." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291389792

    Chicago Manual of Style (17th edition)

ucin1291389792
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© 2010, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.