Immunopathogenesis of Experimental Ulcerative Colitis Is Mediated by Eosinophil Peroxidase

Abstract

The precise role that individual inflammatory cells and mediators play in the development of gastrointestinal (GI) dysfunction and extraintestinal clinical manifestations of ulcerative colitis (UC) is unknown. In this study, we have used a mouse model of UC to establish a central role for eotaxin and, in turn, eosinophils in the development of the immunopathogenesis of this disease. In this model the administration of dextran sodium sulfate (DSS) induces a prominent colonic eosinophilic inflammation and GI dysfunction (diarrhea with blood and shortening of the colon) that resembles UC in patients. GI dysfunction was associated with evidence of eosinophilic cytolytic degranulation and the release of eosinophil peroxidase (EPO) into the colon lumen. By using IL-5 or eotaxin-deficient mice, we show an important role for eotaxin in eosinophil recruitment into the colon during experimental UC. Furthermore, using EPO-deficient mice and an EPO inhibitor resorcinol we demonstrate that eosinophil-derived peroxidase is critical in the development of GI dysfunction in experimental UC. These findings provide direct evidence of a central role for eosinophils and EPO in GI dysfunction and potentially the immunopathogenesis of UC.

Assessment of eosinophils in gastrointestinal inflammatory disease of dogs

“…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.…”

Tissue Eosinophilia in a Mouse Model of Colitis Is Highly Dependent on TLR2 and Independent of Mast Cells

“…14,52 Eosinophil accumulation in the mucosa is a common feature observed during DSS-induced colitis in mice. 16,17 We and others have previously shown that TLR2 signaling in response to the commensal microflora is important in limiting mucosal injury during DSS colitis. 25,26 TLR2-deficient animals have been shown to have a more severe disease development, with an extended time course and slower recovery after cessation of DSS treatment.…”

“…16,17 In untreated mice, there were no significant differences between TLR2 Ϫ/Ϫ and control mice in the levels of IL-5 or CCL11 in the cecum or the mid-colon (Figure 2). After DSS treatment, cecal and colonic CCL11 levels significantly increased in both groups of mice; however.…”

“…14,15 Eosinophil numbers are known to be significantly increased in the mucosa and submucosa of the colon in C57BL/6 mice after dextran sodium sulfate (DSS) treatment, a well characterized and widely used model of inducible colitis. 16,17 Moreover, this eosinophil recruitment was highly dependent on the activity of CCL11. 16,18 Toll-like receptors (TLR) are a family of innate immune pattern recognition receptors that recognize pathogenassociated molecular patterns.…”

“…16,17 Moreover, this eosinophil recruitment was highly dependent on the activity of CCL11. 16,18 Toll-like receptors (TLR) are a family of innate immune pattern recognition receptors that recognize pathogenassociated molecular patterns. Several TLRs are expressed in the large intestine under normal physiological conditions and during inflammation.…”