Jérôme Boué1, Lilian Basso1, Nicolas Cenac1, Catherine Blanpied1, Malvyne Rolli-Derkinderen2, Michel Neunlist2, Nathalie Vergnolle3, Gilles Dietrich4. 1. INSERM Unité 1043, Toulouse, France; CNRS, U5282, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse UPS, Toulouse, France. 2. INSERM Unité 913, Nantes, France; Institut des Maladies de l'Appareil Digestif, Université de Nantes, Nantes, France. 3. INSERM Unité 1043, Toulouse, France; CNRS, U5282, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse UPS, Toulouse, France; Department of Pharmacology and Physiology, University of Calgary, Calgary, Alberta, Canada. 4. INSERM Unité 1043, Toulouse, France; CNRS, U5282, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse UPS, Toulouse, France. Electronic address: gilles.dietrich@inserm.fr.
Abstract
BACKGROUND & AIMS: A dysregulated response of CD4(+) T cells against the microbiota contributes to the development of inflammatory bowel disease. Effector CD4(+) T cells, generated in response to microbe-derived antigens, can reduce somatic inflammatory pain through the local release of opioids. We investigated whether colitogenic CD4(+) T cells that accumulate in the inflamed colon also produce opioids and are able to counteract inflammation-induced visceral pain in mice. METHODS: Colitis was induced via transfer of naive CD4(+)CD45RB(high) T cells to immune-deficient mice or by administration of dextran sulfate sodium. Mice without colitis were used as controls. Samples of colon tissue were collected, and production of opioids by immune cells from inflamed intestine was assessed by quantitative polymerase chain reaction and cytofluorometry analyses. The role of intestinal opioid tone in inflammation-induced visceral hypersensitivity was assessed by colorectal distention. RESULTS: In mice with T cell- or dextran sulfate sodium-induced colitis, colitogenic CD4(+) T cells (T-helper 1 and Th17 cells) accumulated in the inflamed intestine and expressed a high level of endogenous opioids. In contrast, macrophages and epithelial cells did not express opioids; opioid synthesis in the myenteric plexus was not altered on induction of inflammation. In mice with colitis, the local release of opioids by colitogenic CD4(+) T cells led to significant reduction of inflammation-associated visceral hypersensitivity. CONCLUSIONS: In mice, colitogenic Th1 and Th17 cells promote intestinal inflammation and colonic tissue damage but have simultaneous opioid-mediated analgesic activity, thereby reducing abdominal pain.
BACKGROUND & AIMS: A dysregulated response of CD4(+) T cells against the microbiota contributes to the development of inflammatory bowel disease. Effector CD4(+) T cells, generated in response to microbe-derived antigens, can reduce somatic inflammatory pain through the local release of opioids. We investigated whether colitogenic CD4(+) T cells that accumulate in the inflamed colon also produce opioids and are able to counteract inflammation-induced visceral pain in mice. METHODS:Colitis was induced via transfer of naive CD4(+)CD45RB(high) T cells to immune-deficient mice or by administration of dextran sulfate sodium. Mice without colitis were used as controls. Samples of colon tissue were collected, and production of opioids by immune cells from inflamed intestine was assessed by quantitative polymerase chain reaction and cytofluorometry analyses. The role of intestinal opioid tone in inflammation-induced visceral hypersensitivity was assessed by colorectal distention. RESULTS: In mice with T cell- or dextran sulfate sodium-induced colitis, colitogenic CD4(+) T cells (T-helper 1 and Th17 cells) accumulated in the inflamed intestine and expressed a high level of endogenous opioids. In contrast, macrophages and epithelial cells did not express opioids; opioid synthesis in the myenteric plexus was not altered on induction of inflammation. In mice with colitis, the local release of opioids by colitogenic CD4(+) T cells led to significant reduction of inflammation-associated visceral hypersensitivity. CONCLUSIONS: In mice, colitogenic Th1 and Th17 cells promote intestinal inflammation and colonic tissue damage but have simultaneous opioid-mediated analgesic activity, thereby reducing abdominal pain.
Authors: Tereza Bautzova; James R F Hockley; Teresa Perez-Berezo; Julien Pujo; Michael M Tranter; Cleo Desormeaux; Maria Raffaella Barbaro; Lilian Basso; Pauline Le Faouder; Corinne Rolland; Pascale Malapert; Aziz Moqrich; Helene Eutamene; Alexandre Denadai-Souza; Nathalie Vergnolle; Ewan St John Smith; David I Hughes; Giovanni Barbara; Gilles Dietrich; David C Bulmer; Nicolas Cenac Journal: Sci Signal Date: 2018-12-18 Impact factor: 8.192
Authors: Raquel Guerrero-Alba; Eduardo Emmanuel Valdez-Morales; Nestor Nivardo Jiménez-Vargas; Romke Bron; Daniel Poole; David Reed; Joel Castro; Melissa Campaniello; Patrick A Hughes; Stuart M Brierley; Nigel Bunnett; Alan E Lomax; Stephen Vanner Journal: Br J Pharmacol Date: 2018-05-22 Impact factor: 8.739
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