title: A GPBAR1 (TGR5) small molecule agonist shows specific inhibitory effects on myeloid cell activation in vitro and reduces experimental autoimmune encephalitis (EAE) in vivo.
abstract: GPBAR1 is a G protein-coupled receptor that is activated by certain bile acids and plays an important role in the regulation of bile acid synthesis, lipid metabolism, and energy homeostasis. Recent evidence suggests that GPBAR1 may also have important effects in reducing the inflammatory response through its expression on monocytes and macrophages. To further understand the role of GPBAR1 in inflammation, we generated a novel, selective, proprietary GPBAR1 agonist and tested its effectiveness at reducing monocyte and macrophage activation in vitro and in vivo. We have used this agonist, together with previously described agonists to study agonism of GPBAR1, and shown that they can all induce cAMP and reduce TLR activation-induced cytokine production in human monocytes and monocyte-derived macrophages in vitro. Additionally, through the usage of RNA sequencing (RNA-Seq), we identified a select set of genes that are regulated by GPBAR1 agonism during LPS activation. To further define the in vivo role of GPBAR1 in inflammation, we assessed GPBAR1 expression and found high levels on circulating mouse monocytes. Agonism of GPBAR1 reduced LPS-induced cytokine production in mouse monocytes ex vivo and serum cytokine levels in vivo. Agonism of GPBAR1 also had profound effects in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, where monocytes play an important role. Mice treated with the GPBAR1 agonist exhibited a significant reduction in the EAE clinical score which correlated with reduced monocyte and microglial activation and reduced trafficking of monocytes and T cells into the CNS. These data confirm the importance of GPBAR1 in controlling monocyte and macrophage activation in vivo and support the rationale for selective agonists of GPBAR1 in the treatment of inflammatory diseases.
authors: Departments of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Nuruddeen D
authors: ND
authors: Lewis
authors: Departments of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Lori A
authors: LA
authors: Patnaude
authors: Departments of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Josephine
authors: J
authors: Pelletier
authors: Departments of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Donald J
authors: DJ
authors: Souza
authors: Departments of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Susan M
authors: SM
authors: Lukas
authors: Departments of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: F James
authors: FJ
authors: King
authors: Research Networking, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Jonathan D
authors: JD
authors: Hill
authors: Departments of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Dimitria E
authors: DE
authors: Stefanopoulos
authors: Departments of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Kelli
authors: K
authors: Ryan
authors: Departments of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Sudha
authors: S
authors: Desai
authors: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Donna
authors: D
authors: Skow
authors: CardioMetabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc., Biberach, Germany.
authors: Stefan G
authors: SG
authors: Kauschke
authors: CardioMetabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc., Biberach, Germany.
authors: Andre
authors: A
authors: Broermann
authors: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Daniel
authors: D
authors: Kuzmich
authors: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Christian
authors: C
authors: Harcken
authors: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Eugene R
authors: ER
authors: Hickey
authors: Departments of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., Ridgebury, Connecticut, United States of America.
authors: Louise K
authors: LK
authors: Modis
mesh_terms: D000818:Animals; D016466:CHO Cells; D016000:Cluster Analysis; D003412:Cricetulus; D000242:Cyclic AMP; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; C473772:GPBAR1 protein, human; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP