EPIMACASE · THE ROLE OF ELASTASE/ELASTASE INHIBITOR IN DIALOG BETWEEN INTESTINAL EPITHELIAL CELLS AND MACROPHAGES IN INFLAMMATORY BOWEL DISEASES CONTEXT
FP7 — People (Marie Curie Actions)
- Duration
- 2014-08-06 → 2016-08-05
- EU contribution
- €246,114
- Participants
- 1
- Scheme
- MC-IOF
Lines connect the coordinator with its partners.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
Inflammatory Bowel Diseases (IBD) are chronic disorders for which aetiology is unknown and only palliative care is available for patients. In Europe, 2.2 million people suffered of ulcerative colitis or Crohn's disease in Europe, the socio-economic impact of IBD is very heavy. Thus, the development of new and more effective treatments for IBD depends upon a better understanding of the regulation of inflammatory response.The aims of this project are both: firstly, provide evidence of contribution of secreted elastase from intestinal epithelial cells (IEC) to over activation of macrophages in IBD and establish molecular actors of this crosstalk; secondly decipher the protective properties against colitis of ELAFIN, an elastase inhibitor, through modulation of macrophage activities. The fellow will develop in vitro and in vivo experiments to establish the role of elastolytic balance in the dialog between IEC and macrophages in relation to IBD.Our data raise the possibility that intestinal IEC are major regulators of proteolytic homeostasis by secreting proteases and protease inhibitors, which then can interfere with all biological functions of the gut, including immune functions. In IBD, secreted hyperactive elastase could participate to the dialogue between epithelium and other mucosal cells such as macrophages. Our analysis of elastase homeostasis aims to identify control points in the mechanisms of disease that could be addressed by development of a novel therapeutic approach for IBD.The fellow holds a junior investigator position at a French Institution. This program will allow her to develop complementary and transferable skills and to successfully build-up and conduct a ground-breaking research project in the field of human digestive health. This foreign experience is a necessary step on the road to complete independence for her. Thanks to this program, she would be in an optimal position to create an independent research group upon her return to Europe.
Original text from CORDIS.
Participants
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union