Eosinophils alter colonic epithelial barrier function: role for major basic protein

Abstract

Mucosal eosinophils increase in a number of gastrointestinal diseases that are often associated with altered epithelial barrier function, including food allergic enteropathies and inflammatory bowel diseases. Although eosinophils are known to secrete biologically active mediators including granule proteins, their role in gastrointestinal diseases is uncertain. The aim of this study was to determine the impact of eosinophils on intestinal barrier function. Epithelial barrier function was determined in a coculture of eosinophils and T84 epithelial cells and in a murine model of T helper (Th) type 2-mediated colitis. Coculture conditions resulted in decreased transepithelial resistance (TER) and increased transepithelial flux. Cell-free coculture supernatants contained a > or =5-kDa soluble factor that also diminished TER; these supernatants contained the eosinophil-granule proteins major basic protein (MBP) and eosinophil-derived neurotoxin (EDN). T84 barrier function decreased significantly when basolateral surfaces were exposed to native human MBP but not EDN. Additional studies identified downregulation of the tight junctional molecule occludin as at least one mechanism for MBP action. MBP-null mice were protected from inflammation associated with oxazolone colitis compared with wild-type mice. In conclusion, MBP decreases epithelial barrier function and in this manner contributes to the pathogenesis of inflammatory bowel diseases.

Exacerbation of Oxazolone Colitis by Infection with the Helminth Hymenolepis diminuta

“…[23][24][25][26] The correlation of increased numbers of eosinophils in inflamed tissue and the ability of eosinophil-derived molecules (eg, major basic protein) to cause tissue damage has led to the supposition that these cells contribute to inflammation: a postulate supported by data from animal models of colitis. [27][28][29][30] However, the release of TGF␤ from eosinophils can promote tissue restitution. 31 Indeed, recognition of multiple functional phenotypes within a given type of immune cell lineage 32 raises the possibility that subgroups of eosinophils could exert anti-inflammatory effects.…”

“…18 Furthermore, major basic protein was found to increase murine colonic epithelial permeability and exaggerate colitis. 29 Also, preliminary evidence suggests that eosinophil activation results in increases in epithelial permeability in biopsy specimens from patients with ulcerative colitis. 41 Thus, the current study (Figure 8) adds to a small body amount of data suggesting that one mechanism by which eosinophils could enhance intestinal inflammation is by the induction of decreases in epithelial barrier function.…”

Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

“…97 It is important to note here the ability of eosinophils to alter intestinal permeability and the mechanisms and mediators involved. 98 Barrier function has been shown to be affected by eosinophil-derived major basic protein (MBP) through downregulation of occludin in a mast cell independent fashion. 98 The neuropeptide substance P (SP) has been found to induce the release of vasoactive mediators from mast cells, macrophages, and T cells, contributing to chloride secretion, enhanced intestinal permeability, and vascular leakiness.…”

Assessment of eosinophils in gastrointestinal inflammatory disease of dogs

“…For example, eosinophil‐derived TGF‐β is linked to tissue remodeling and induction of the extracellular matrix protein periostin in patient biopsy specimens which increases eosinophil infiltration in the mucosal layer, thus facilitating disease pathogenesis 26, 27. Furthermore, as indicated above, granule proteins such as eosinophil cationic protein, Epx, and major basic protein released by activated eosinophils during inflammation can contribute to tissue damage (alter barrier function) and dysfunction (diarrhea with bleeding) 9, 10, 11, 12. Deficiency of eotaxin‐1, the eosinophil‐specific chemokine, or blockade of its receptor (CCR3) resulting in depletion of eosinophils has been shown to attenuate inflammation in experimental models of IBD,9, 28 thus supporting the overall importance of eosinophil involvement in EGID.…”

“…The presence of an increased number of degranulated eosinophils in the upper and lower LP may be a previously unrecognized feature of IBD. Previous studies indicate that eosinophil granule proteins (eg, eosinophil cationic protein, major basic protein) released by activated eosinophils contribute to tissue damage and inflammation during GI disorders and may be indicative of active ongoing disease 3, 10, 30, 33, 34…”