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The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype Of

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The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype Of The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype of Intestinal Macrophages and Activation of GPBAR1 Rescues Mice from Murine Colitis This information is current as of September 28, 2021. Michele Biagioli, Adriana Carino, Sabrina Cipriani, Daniela Francisci, Silvia Marchianò, Paolo Scarpelli, Daniele Sorcini, Angela Zampella and Stefano Fiorucci J Immunol 2017; 199:718-733; Prepublished online 12 June 2017; Downloaded from doi: 10.4049/jimmunol.1700183 http://www.jimmunol.org/content/199/2/718 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2017/06/10/jimmunol.170018 Material 3.DCSupplemental References This article cites 40 articles, 6 of which you can access for free at: http://www.jimmunol.org/content/199/2/718.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Bile Acid Receptor GPBAR1 Regulates the M1/M2 Phenotype of Intestinal Macrophages and Activation of GPBAR1 Rescues Mice from Murine Colitis Michele Biagioli,* Adriana Carino,* Sabrina Cipriani,† Daniela Francisci,† Silvia Marchiano`,* Paolo Scarpelli,‡ Daniele Sorcini,x Angela Zampella,{ and Stefano Fiorucci‖ 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 Downloaded from 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+, F4/802)toan alternatively activated (CD11b+, CCR72, F4/80+) phenotype, reduced the expression of inflammatory genes (TNF-a, IFN-g, IL-1b, 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 Gpbar12/2 mice. Exposure to BAR501 increased the colonic expression of http://www.jimmunol.org/ IL-10 and TGF-b mRNAs and the percentage of CD4+/Foxp3+ cells. The beneficial effects of BAR501 were lost in Il-102/2 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 macro- phages, 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. The Journal of Immunology, 2017, 199: 718–733. nflammatory bowel diseases (IBDs) encompass two highly the lack of response or loss of response to drugs, because of in- prevalent chronic disorders, Crohn’s disease and ulcerative tolerance or severe side effects that require cessation of therapy. by guest on September 28, 2021 I colitis, which result from a dysregulated intestinal immune Recently, novel approaches that target leukocyte trafficking to the response to Ags derived from the intestinal microbiota in geneti- gut by inhibiting integrins, chemokines, and chemokine receptors cally predisposed individuals (1, 2). IBDs have traditionally been (4) have been developed, but 30–40% of patients fail to respond to treated with nonspecific immunosuppressive drugs (e.g., cortico- these approaches in clinical trials. Therefore, there is a clinical steroids or azathioprine), anti-inflammatory agents (e.g., 5-amino- need for new treatments based on therapies that are able to se- salicylic acid), and, more recently, with anti–TNF-a agents (3). lectively regulate the intestinal immune response, overcoming the These treatments have shown efficacy in mild to severe disease; limitations of current therapies. however, a large percentage of patients with severe illness do not Bile acids, the end product of cholesterol metabolism, play an achieve complete remission or cannot maintain remission due to essential role in maintaining liver and intestinal homeostasis (5, 6). Primary bile acids (chenodeoxycholic acid [CDCA] and cholic acid) and secondary bile acids (deoxycholic acid [DCA] and *Department of Surgical and Biomedical Sciences, University of Perugia, Perugia lithocholic acid [LCA]), as well as their glycine and taurine 06132, Italy; †Department of Medicine, University of Perugia, Perugia 06132, Italy; ‡Department of Experimental Medicine, Laboratory of Biotechnology, University of conjugates, are signaling molecules that exert a variety of regu- Perugia, Perugia 06132, Italy; xSection of Pharmacology, Department of Medicine, latory functions by activating a family of cell surface and nuclear University of Perugia, Perugia 06132, Italy; {Department of Pharmacy, University of ‖ receptors collectively known as the bile acid–activated receptors Naples “Federico II,” Naples 80181, Italy; and Department of Surgical and Biomed- ical Sciences, University of Perugia, Perugia 06132, Italy (BARs) (7). The two best characterized members of the BAR ORCIDs: 0000-0003-2341-9528 (A.C.); 0000-0001-6583-3693 (P.S.). family are the G protein–coupled receptor GPBAR1 (also known Received for publication February 7, 2017. Accepted for publication May 16, 2017. as TGR5 or M-BAR) and the nuclear receptor FXR (8–11). Address correspondence and reprint requests to Prof. Stefano Fiorucci, Department GPBAR1 was the first transmembrane G protein–coupled receptor of Surgical and Biomedical Sciences, University of Perugia, Square L. Severi 1, shown to be activated by bile acids, with DCA and LCA, as well Palace B 3rd Floor, Perugia 06132, Italy. E-mail address: stefano.fi[email protected] as their taurine and glycine conjugates, functioning as bona fide The online version of this article contains supplemental material. physiological ligands (12, 13). In the human body, the expression Abbreviations used in this article: BAR, bile acid–activated receptor; CDAI, Colitis of GPBAR1 is essentially restricted to the small intestine, gall- Disease Activity Index; CDCA, chenodeoxycholic acid; ChIP, chromatin immuno- precipitation; CRE, cAMP-responsive element; DCA, deoxycholic acid; FMO, fluo- bladder, adipose tissues, and immune system. In response to li- rescence minus one; IBD, inflammatory bowel disease; LCA, lithocholic acid; M1, gands, GPBAR1 signals by increasing intracellular concentrations classically activated; M2, alternatively activated; siRNA, small interfering RNA; of cAMP, leading to rapid phosphorylation of downstream kinases TNBS, trinitrobenzenesulfonic acid; Treg, regulatory T cell. that are responsible for the nongenomic effects exerted by this Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 receptor (14). In addition, GPBAR1 exerts genomic effects that www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700183 The Journal of Immunology 719 are mediated by binding of a CREB to a cAMP-responsive ele- brief, mice were fasted for 12 h overnight (day 21). The following day ment (CRE) in the promoter of target genes (15, 16). (day 0), under profound sedation induced by the administration of a In the immune system, GPBAR1 is primarily expressed by cells mixture of tiletamine hypochloride and zolazepam hypochloride/xylazine (50/5 mg/kg), a 3.5 F catheter was inserted into the colon for up to 4 cm of myeloid origin, whereas T and B cells express the receptor at from the anus, and 1 mg of trinitrobenzenesulfonic acid (TNBS) (Sigma- very low levels. In macrophages derived from peripheral blood and Aldrich, St. Louis, MO) in 50% ethanol was administered via the catheter liver macrophages, activation of GPBAR1 counteracts the activity into the colon lumen using a 1-ml syringe (injection volume of 100 ml). of CD14/TLR4, decreasing the phagocytic capacity and production Control mice received 50% ethanol alone. Animals were monitored daily for diarrhea, loss of body weight, presence of blood in the stool, and of proinflammatory cytokines TNF-a, IL-1a, IL-1b, and IL-6 (15, survival. At the end of the experiment, 4 d after the administration of 16). In the intestine, GPBAR1 oversees a variety of homeostatic TNBS, surviving mice were sacrificed, blood samples were collected by functions, and we have previously shown that mice harboring cardiac puncture, and the colon was excised, weighed,
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