The role of retinoic acid signalling in Trichuris muris-driven gut inflammation

Abstract

Trichuris muris is a helminth parasite of mice which infects the caecum and colon. T. muris infection in the mouse is used as a model of infection of man with the human whipworm infection Trichuris trichiura. Infection with this parasite results in intestinal inflammation that has been compared to the inflammatory situation observed in human inflammatory bowel disease (IBD). Retinoic acid, the major metabolite of vitamin A, has been shown to have many affects on the immune system including regulating inflammation. Further, vitamin A supplementation of worm infected individuals is often practised in areas of T. muris prevalence, although the implications of this are not yet fully understood. Retinoic acid signals through the nuclear hormone receptors retinoic acid receptor (RAR) and the retinoid X receptor (RXR) to modify the transcription of genes. In this thesis I investigate the role of retinoic acid signalling on the intestinal inflammation caused by infection with the T. muris parasite, specifically focusing on the role of RXR and RAR signalling through agonism or antagonism of these receptors with synthetic compounds, as well as monitoring the production of retinoic acid throughout the course of infection.RXR has previously demonstrated many effects on inflammatory processes including beneficially regulating inflammation in chemical model of mouse colitis. Using the synthetic RXR antagonist, HX531, we observe that antagonism of RXR in T. muris infected AKR mice results in an exaggerated pathology, demonstrated by increased thickening of the colonic muscle wall, an increased inflammatory infiltrate and elevated levels of TNF-alpha, although, not all of these pathological changes are observed with RXR antagonist treatment of T. muris infected C57BL/6 mice. We also show that TNF-alpha may be a key cytokine in regulating some of these RXR driven pathological effects and that, although RXR signalling plays a role in regulating macrophage biology, the macrophage is not essential for mediating the effects of RXR in vivo. Our studies reveal no effects on the inflammatory processes during chronic T. muris infection with agonism of RXR using the synthetic RXR agonist, HX630. Importantly, we show, that rather than playing an anti inflammatory role, the RARalpha/beta agonist Am80 actually exacerbates helminth driven inflammation, as demonstrated by an exaggerated crypt hyperplasia and an increased CD4+ cellular infiltrate, and that these pro inflammatory effects are IL 6 dependent, and occur across genetic backgrounds. We further show that RAR regulated pathology is dependent on the presence of T and/or B cells and suggest that the CD4+ T cell may be a key cell type in mediating the effects of RAR signalling.Our results show, for the first time, that gut dendritic cells (DCs) and macrophages have the potential to produce retinoic acid and that this is decreased during on going T. muris infection. Further, we identify a role for RXR signalling in the regulation of the expression of key enzymes critical for the production of retinoic acid in macrophages.Overall, we conclude that the effects of RXR signalling during T. muris driven gut inflammation are complex, varied and may depend on genetic background, which may be a barrier if RXR is to be a useful therapeutic target for IBD treatment in man. Our finding that RAR activation leads to exaggerated intestinal pathology during T. muris infection adds caution to the practise of supplementing parasite infected individuals with vitamin A.

Date of Award	3 Jan 2012
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Kathryn Else (Supervisor)