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T-lymphocyte-derived enkephalins reduce Th1/Th17 colitis and associated pain in mice

  • Original Article—Alimentary Tract
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Abstract

Background

Endogenous opioids, including enkephalins, are fundamental regulators of pain. In inflammatory conditions, the local release of opioids by leukocytes at the inflammatory site inhibits nociceptor firing, thereby inducing analgesia. Accordingly, in chronic intestinal Th1/Th17-associated inflammation, enkephalins released by colitogenic CD4+ T lymphocytes relieve inflammation-induced visceral pain. The present study aims to investigate whether mucosal T-cell-derived enkephalins also exhibit a potent anti-inflammatory activity as described for exogenous opioid drugs in Th1/Th17-associated colitis.

Methods

The anti-inflammatory effects of endogenous opioids were investigated in both Th1/Th17-associated (transfer of CD4+CD45RBhigh T lymphocytes) and Th2-associated (oxazolone) colitis models in mice. Inflammation-induced colonic damage and CD4+ T cell subsets were compared in mice treated or not treated with naloxone methiodide, a peripheral antagonist of opioid receptors. The anti-inflammatory activity of T-cell-derived enkephalins was further estimated by comparison of colitis severity in immunodeficient mice into which naïve CD4+CD45RBhigh T lymphocytes originating from wild-type or enkephalin-knockout mice had been transferred.

Results

Peripheral opioid receptor blockade increases the severity of Th1/Th17-induced colitis and attenuates Th2 oxazolone colitis. The opposite effects of naloxone methiodide treatment in these two models of intestinal inflammation are dependent on the potency of endogenous opioids to promote a Th2-type immune response. Accordingly, the transfer of enkephalin-deficient CD4+CD45RBhigh T lymphocytes into immunodeficient mice exacerbates inflammation-induced colonic injury.

Conclusions

Endogenous opioids, including T-cell-derived enkephalins, promote a Th2-type immune response, which, depending on the context, may either attenuate (Th1/Th17-associated) or aggravate (Th2-associated) intestinal inflammation.

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Acknowledgements

The authors thank the ANEXPLO (UMR 006) animal care facility (Y. Barreira and S. Appolinaire), Aninfimip, an EquipEx (Equipement d’Excellence) supported by the French government through the Investments for the Future program (ANR-11-EQPX-0003), and the U1043 flow cytometry facility (F. L’Faqihi-Olive and V. Duplan-Eche). This work was supported by the Institut National de la Santé et de la Recherche Médicale, Université Paul Sabatier, Toulouse III, and the Association François Aupetit.

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Authors and Affiliations

  1. Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Paul Sabatier (UPS), Toulouse, France

    Lilian Basso, Arnaud Bessac, Jérôme Boué, Catherine Blanpied, Nicolas Cenac & Gilles Dietrich

  2. Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paul Sabatier (UPS), Toulouse, France

    Laure Garnier & Sophie Laffont

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  1. Lilian Basso
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Correspondence to Gilles Dietrich.

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Basso, L., Garnier, L., Bessac, A. et al. T-lymphocyte-derived enkephalins reduce Th1/Th17 colitis and associated pain in mice. J Gastroenterol 53, 215–226 (2018). https://doi.org/10.1007/s00535-017-1341-2

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  • DOI: https://doi.org/10.1007/s00535-017-1341-2

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