Increased susceptibility of MMP19 deficient mice to DSS-induced colitis provides novel insights into pathogenesis of intestinal inflammation

Introduction: Matrix metalloproteinase-19 (MMP19) belongs to a family of the zinc-dependent endopeptidases, which are known to remodel extracellular matrix (ECM) and process a number of cell surface receptors, their ligands, and adhesion molecules. These proteolytical activities have direct impact on cell behaviour, proliferation, and survival. Beside their role in matrix processing MMPs are important in the development and outcome of inflammatory responses by activating and releasing cytokines, establishing a chemokine gradient, controlling cell migration and survival, and contributing to epidermal barrier function. MMP19 was found to be constitutively secreted by various tissues and cell types and shown to be upregulated in skin under inflammatory conditions and during cancer progression. It was also shown that MMP19 controls delayed-type of hypersensitivity in the skin. Dependent on the cell and tissue type MMP19 can play either a suppressor role or can exacerbate the disease outcome.

Aim: In this study, we aimed to analyse the functional role of MMP19 in intestinal inflammation by using MMP19-deficient mice in a mouse model of chemically-induced colitis.

Material and methods: Dextran sodium sulphate (DSS) was administered to age-matched male wild-type (WT) and MMP-19 deficient mice (C57Bl/6 background) at a concentration of 2% (w/v) in drinking water for 6 days to induce acute colitis. For analysing the healing process mice were given 2% DSS for 5 days followed by a 10 day recovery period using normal drinking water. The administration of two cycles of DSS (2% DSS for 4 days, 10 days water) results in chronic colitis. Colitis severity was assessed by changes in body weight, stool consistency and occult bleeding. Furthermore, colon length was determined and histological analysis of its proximal, middle and distal parts was performed. Cytokine concentrations (IL-6, IL-1â, KC, MCP-1) in plasma and supernatants of colon tissue explants were measured by Luminex.

Results: During the course of DSS-induced acute colitis, the MMP19-deficient mice lost significantly more weight than the WT mice (22%±5% vs. 12%±3%, p<0.08). Also, the disease activity index (DAI) that included also the severity of diarrhoea and the amount of blood in stool was remarkably higher in MMP19-deficient mice. Histologically, the MMP19-deficient mice showed reduced infiltration of neutrophils into the colonic tissue during the course of colitis but increased lesion extent, ulceration and oedema. The differences between WT and knockout mice were even more striking in the recovery phase of the colitis as MMP19-deficient animals showed only 65% survival. During the chronic colitis just 50% survived and they did not regain their initial weight. MMP19-deficient animals showed elevated levels of pro-inflammatory cytokines in blood plasma and supernatants of ex vivo cultures of colonic tissues during all phases of colitis.

Conclusion: The exacerbation of the colitis in the MMP19-deficient mice together with elevated concentrations of pro-inflammatory cytokines derived from colonic tissue suggests that MMP19 plays an essential role in maintenance of intestinal homeostasis. This may have important implications for the two major inflammatory conditions of the intestine in humans, Crohn‘s disease and ulcerative colitis.