P0181 Modulating macrophage activity via NAAA pharmacological inhibition: a therapeutic strategy for intestinal fibrosis

Le résumé fourni par la source

Abstract Background Intestinal fibrosis, a frequent complication of inflammatory bowel disease, is characterized by stricture formation with no pharmacological treatment to date. N-acylethanolamine acid amidase (NAAA) is responsible for the hydrolysis of acylethanolamides (AEs, eg, palmitoylethanolamide and oleoylethanolamide). Here, we investigated NAAA and AE signalling in gut fibrosis. Methods NAAA and AE signalling were evaluated in human intestinal specimens from patients with stenotic Crohn’s disease (CD). Gut fibrosis was induced by 2,4,6-trinitrobenzenesulfonic acid, monitored by colonoscopy, and assessed by qRT-PCR, histological analyses, and confocal microscopy. Immune cells in mesenteric lymph nodes were analysed by FACS. Colonic fibroblasts were cultured in conditioned media derived from polarized or non-polarized bone marrow-derived macrophages (BMDMs). IL-23 signalling was evaluated by qRT-PCR, ELISA, FACS, and western blot in BMDMs and in lamina propria CX3CR1+ cells. Results In ileocolonic human CD strictures, increased transcript expression of NAAA was observed with a decrease in its substrates oleoylethanolamide and palmitoylethanolamide. NAAA inhibition reduced intestinal fibrosis in vivo. More in-depth studies revealed modulation of the immune response related to IL-23 following NAAA inhibition. The antifibrotic actions of NAAA inhibition are mediated by Mφ and M2 macrophages that indirectly affect fibroblast collagenogenesis. NAAA inhibitor AM9053 normalized IL-23 signalling in BMDMs and in lamina propria CX3CR1+ cells. Conclusion Our findings provide new insights into the pathophysiological mechanism of intestinal fibrosis and identify NAAA as a promising target for the development of therapeutic treatments to alleviate CD-related fibrosis.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.