Essential role for mast cell tryptase in acute experimental colitis

Abstract

Patients with inflammatory bowel disease (IBD) have increased numbers of human tryptase-β (hTryptase-β)-positive mast cells (MCs) in the gastrointestinal tract. The amino acid sequence of mouse mast cell protease (mMCP)-6 is most similar to that of hTryptase-β. We therefore hypothesized that this mMCP, or the related tryptase mMCP-7, might have a prominent proinflammatory role in experimental colitis. The dextran sodium sulfate (DSS) and trinitrobenzene sulfonic acid (TNBS) colitis models were used to evaluate the differences between C57BL/6 (B6) mouse lines that differ in their expression of mMCP-6 and mMCP-7 with regard to weight loss, colon histopathology, and endoscopy scores. Microarray analyses were performed, and confirmatory real-time PCR, ELISA, and/or immunohistochemical analyses were carried out on a number of differentially expressed cytokines, chemokines, and matrix metalloproteinases (MMPs). The mMCP-6-null mice that had been exposed to DSS had significantly less weight loss as well as significantly lower pathology and endoscopy scores than similarly treated mMCP-6-expressing mice. This difference in colitis severity was confirmed endoscopically in the TNBS-treated mice. Evaluation of the distal colon segments revealed that numerous proinflammatory cytokines, chemokines that preferentially attract neutrophils, and MMPs that participate in the remodeling of the ECM were all markedly increased in the colons of DSS-treated WT mice relative to untreated WT mice and DSS-treated mMCP-6-null mice. Collectively, our data show that mMCP-6 (but not mMCP-7) is an essential MC-restricted mediator in chemically induced colitis and that this tryptase acts upstream of many of the factors implicated in IBD.

Importance of Mast Cell Prss31/Transmembrane Tryptase/Tryptase-γ in Lung Function and Experimental Chronic Obstructive Pulmonary Disease and Colitis

“…On days 6 and 7, the treated mice were given normal drinking water. Exposure of WT B6 mice to these experimental conditions results in substantial inflammation and a 7-15% weight loss without mortality (13).…”

“…Prss31 therefore has a substrate specificity that overlaps that of its tetramer-forming family members. Although the function of Prss31 is not known, the tetramer-forming tryptases mMCP-6 and mMCP-7 have prominent beneficial roles in innate immunity (9 -11) but substantial adverse roles in numerous inflammatory diseases (12)(13)(14).…”

“…Employing a previously developed experimental protocol (13,36), the two groups of animals were exposed to dextran sodium sulfate (DSS) (36 -50 kDa; MP Biomedicals) at a concentration of 2.0% in their drinking water for 5 days. On days 6 and 7, the treated mice were given normal drinking water.…”

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

“…There is also evidence of a pathogenic role for the mouse mast cell protease (mMCP)-6, the mouse homolog of the human tryptase, in dextran sodium sulfate (DSS)-induced colitis (15), but no conclusive data exist about the actual role of mMCP-6 in colon inflammation. MCs are known to accumulate in the inflamed gut of IBD patients (16)(17)(18).…”

“…Colons were dissected at different time points during the acute and recovery phase (day [11][12][13][14][15][16][17] and the frequency of c-kit and FceRI double-positive cells in CD45 þ CD11b À infiltrating cells assessed (Fig. 1A).…”