Final Report Summary - EPIMACASE (THE ROLE OF ELASTASE/ELASTASE INHIBITOR IN DIALOG BETWEEN INTESTINAL EPITHELIAL CELLS AND MACROPHAGES IN INFLAMMATORY BOWEL DISEASES CONTEXT)
The aim of the present proposal was to fully investigate the role of intestinal proteolytic homeostasis in the differentiation of mucosal macrophages. Considering that most resident Mϕ are in the lamina propria below the epithelial monolayer, it was hypothesised that the IEC play a major role in the education process of intestinal Mϕ. In parallel, the phenotype and behaviour of mucosal macrophages change dramatically upon inflammation or protective immune responses. Thus, the effects of epithelial elastase on macrophages differentiation in the context of IBD were examined.
Our preliminary data on murine Mϕ showed that epithelial elastase enhanced pro-inflammatory cytokines release when Mϕ are polarized towards a pro-inflammatory (M1) phenotype and blocked up-regulation of typical markers of immunoregulatory (M2) phenotype. The process involved the proteolytic cleavage of a transmembrane receptor, named PAR2.
In vivo, colonic administration of adenovirus encoding human epithelial elastase confirmed that over-expression in colonic epithelial cells induced and worsened colitis. Notably, Mϕ massively colonized the lamina propria. Therefore, it is now clear that epithelial elastase activity modulate the Mϕ physiology. Today, development of transgenic animal, in which epithelial elastase gene is invalided or up-regulated, will permit to fully decipher the role of epithelial elastase in intestinal homeostasis.
Following the study about elastolytic balance in intestinal mucosae, we hope to identify control points in the mechanisms of disease that could be addressed by the development of a novel therapeutic approach for IBD.