Final Report Summary - EPIMACASE (THE ROLE OF ELASTASE/ELASTASE INHIBITOR IN DIALOG BETWEEN INTESTINAL EPITHELIAL CELLS AND MACROPHAGES IN INFLAMMATORY BOWEL DISEASES CONTEXT)
Inflammatory Bowel Diseases (IBD) (main forms being Crohn’s disease and ulcerative colitis) are chronic inflammatory disorders of the gut that afflicts 2.2 millions of persons in Europe. The clinical course of these pathologies evolves through acute flare periods and remission phases. To date, the etiological triggers of inflammation are unknown; however it likely results from the combinatorial input of predisposing genetic factors, of the microbiota, and of an ill-mounted immune response. When considering the factors involved in tissue architecture and remodelling, proteases occupy the very first place. As a matter of fact, the inflamed intestinal epithelium secretes more elastolytic activity and releases less elastase inhibitor, ELAFIN. Therefore, it is clear that proteolytic homeostasis of the gut is disrupted in IBD, and that the intestinal epithelium could exert a pivotal role in this homeostasis. Interestingly, It is observed not only in inflamed area but interestingly, also in non-inflamed areas. Epithelial elastase hyperactivity could participate to the induction of chronic intestinal inflammation. This concept constitutes the basis of this project.
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.
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.
