The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype of Intestinal Macrophages and Activation of GPBAR1 Rescues Mice from Murine Colitis (original) (raw)
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Department of Surgical and Biomedical Sciences, University of Perugia
, Perugia 06132,
Italy
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Department of Surgical and Biomedical Sciences, University of Perugia
, Perugia 06132,
Italy
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Department of Medicine, University of Perugia
, Perugia 06132,
Italy
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Department of Medicine, University of Perugia
, Perugia 06132,
Italy
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Department of Surgical and Biomedical Sciences, University of Perugia
, Perugia 06132,
Italy
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Department of Experimental Medicine, Laboratory of Biotechnology, University of Perugia
, Perugia 06132,
Italy
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Section of Pharmacology, Department of Medicine, University of Perugia
, Perugia 06132,
Italy
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Department of Pharmacy, University of Naples “Federico II”
, Naples 80181,
Italy
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Department of Surgical and Biomedical Sciences, University of Perugia
, Perugia 06132,
Italy
Address correspondence and reprint requests to Prof. Stefano Fiorucci, Department of Surgical and Biomedical Sciences, University of Perugia, Square L. Severi 1, Palace B 3rd Floor, Perugia 06132, Italy. E-mail address: [email protected]
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Received:
07 February 2017
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Michele Biagioli, Adriana Carino, Sabrina Cipriani, Daniela Francisci, Silvia Marchianò, Paolo Scarpelli, Daniele Sorcini, Angela Zampella, Stefano Fiorucci, The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype of Intestinal Macrophages and Activation of GPBAR1 Rescues Mice from Murine Colitis, The Journal of Immunology, Volume 199, Issue 2, July 2017, Pages 718–733, https://doi.org/10.4049/jimmunol.1700183
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Abstract
GPBAR1 (TGR5 or M-BAR) is a G protein–coupled receptor for secondary bile acids that is highly expressed in monocytes/macrophages. In this study, we aimed to determine the role of GPBAR1 in mediating leukocyte trafficking in chemically induced models of colitis and investigate the therapeutic potential of BAR501, a small molecule agonist for GPBAR1. These studies demonstrated that GPBAR1 gene ablation enhanced the recruitment of classically activated macrophages in the colonic lamina propria and worsened the severity of inflammation. In contrast, GPBAR1 activation by BAR501 reversed intestinal inflammation in the trinitrobenzenesulfonic acid and oxazolone models by reducing the trafficking of Ly6C+ monocytes from blood to intestinal mucosa. Exposure to BAR501 shifted intestinal macrophages from a classically activated (CD11b+, CCR7+, F4/80−) to an alternatively activated (CD11b+, CCR7−, F4/80+) phenotype, reduced the expression of inflammatory genes (TNF-α, IFN-γ, IL-1β, IL-6, and CCL2 mRNAs), and attenuated the wasting syndrome and severity of colitis (≈70% reduction in the Colitis Disease Activity Index). The protective effect was lost in Gpbar1−/− mice. Exposure to BAR501 increased the colonic expression of IL-10 and TGF-β mRNAs and the percentage of CD4+/Foxp3+ cells. The beneficial effects of BAR501 were lost in Il-10−/− mice. In a macrophage cell line, regulation of IL-10 by BAR501 was GPBAR1 dependent and was mediated by the recruitment of CREB to its responsive element in the IL-10 promoter. In conclusion, GPBAR1 is expressed in circulating monocytes and colonic macrophages, and its activation promotes a IL-10–dependent shift toward an alternatively activated phenotype. The targeting of GPBAR1 may offer therapeutic options in inflammatory bowel diseases.
Copyright © 2017 by The American Association of Immunologists, Inc.
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