title: S1P2/G12/13 Signaling Negatively Regulates Macrophage Activation and Indirectly Shapes the Atheroprotective B1-Cell Population.
abstract: OBJECTIVE
  Monocyte/macrophage recruitment and activation at vascular predilection sites plays a central role in the pathogenesis of atherosclerosis. Heterotrimeric G proteins of the G12/13 family have been implicated in the control of migration and inflammatory gene expression, but their function in myeloid cells, especially during atherogenesis, is unknown.
  
  
  RESULTS
  Mice with myeloid-specific deficiency for G12/13 show reduced atherosclerosis with a clear shift to anti-inflammatory gene expression in aortal macrophages. These changes are because of neither altered monocyte/macrophage migration nor reduced activation of inflammatory gene expression; on the contrary, G12/13-deficient macrophages show an increased nuclear factor-κB-dependent gene expression in the resting state. Chronically increased inflammatory gene expression in resident peritoneal macrophages results in myeloid-specific G12/13-deficient mice in an altered peritoneal micromilieu with secondary expansion of peritoneal B1 cells. Titers of B1-derived atheroprotective antibodies are increased, and adoptive transfer of peritoneal cells from mutant mice conveys atheroprotection to wild-type mice. With respect to the mechanism of G12/13-mediated transcriptional control, we identify an autocrine feedback loop that suppresses nuclear factor-κB-dependent gene expression through a signaling cascade involving sphingosine 1-phosphate receptor subtype 2, G12/13, and RhoA.
  
  
  CONCLUSIONS
  Together, these data show that selective inhibition of G12/13 signaling in macrophages can augment atheroprotective B-cell populations and ameliorate atherosclerosis.
authors.affiliation: From the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.G., D.T., K.T., J.A.J., K.K.S., N.W.); Pharmazentrum Frankfurt/ZAFES, Clinical Pharmacology (N.F.B., G.G.) and Centre for Molecular Medicine, Medical Faculty (N.W.), J.W. Goethe University Frankfurt, Frankfurt, Germany; and Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (C.J.B.).
authors.forename: Myriam
authors.initials: M
authors.lastname: Grimm
authors.affiliation: From the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.G., D.T., K.T., J.A.J., K.K.S., N.W.); Pharmazentrum Frankfurt/ZAFES, Clinical Pharmacology (N.F.B., G.G.) and Centre for Molecular Medicine, Medical Faculty (N.W.), J.W. Goethe University Frankfurt, Frankfurt, Germany; and Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (C.J.B.).
authors.forename: Denise
authors.initials: D
authors.lastname: Tischner
authors.affiliation: From the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.G., D.T., K.T., J.A.J., K.K.S., N.W.); Pharmazentrum Frankfurt/ZAFES, Clinical Pharmacology (N.F.B., G.G.) and Centre for Molecular Medicine, Medical Faculty (N.W.), J.W. Goethe University Frankfurt, Frankfurt, Germany; and Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (C.J.B.).
authors.forename: Kerstin
authors.initials: K
authors.lastname: Troidl
authors.affiliation: From the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.G., D.T., K.T., J.A.J., K.K.S., N.W.); Pharmazentrum Frankfurt/ZAFES, Clinical Pharmacology (N.F.B., G.G.) and Centre for Molecular Medicine, Medical Faculty (N.W.), J.W. Goethe University Frankfurt, Frankfurt, Germany; and Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (C.J.B.).
authors.forename: Julián
authors.initials: J
authors.lastname: Albarrán Juárez
authors.affiliation: From the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.G., D.T., K.T., J.A.J., K.K.S., N.W.); Pharmazentrum Frankfurt/ZAFES, Clinical Pharmacology (N.F.B., G.G.) and Centre for Molecular Medicine, Medical Faculty (N.W.), J.W. Goethe University Frankfurt, Frankfurt, Germany; and Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (C.J.B.).
authors.forename: Kishor K
authors.initials: KK
authors.lastname: Sivaraj
authors.affiliation: From the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.G., D.T., K.T., J.A.J., K.K.S., N.W.); Pharmazentrum Frankfurt/ZAFES, Clinical Pharmacology (N.F.B., G.G.) and Centre for Molecular Medicine, Medical Faculty (N.W.), J.W. Goethe University Frankfurt, Frankfurt, Germany; and Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (C.J.B.).
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós Bouzas
authors.affiliation: From the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.G., D.T., K.T., J.A.J., K.K.S., N.W.); Pharmazentrum Frankfurt/ZAFES, Clinical Pharmacology (N.F.B., G.G.) and Centre for Molecular Medicine, Medical Faculty (N.W.), J.W. Goethe University Frankfurt, Frankfurt, Germany; and Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (C.J.B.).
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: From the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.G., D.T., K.T., J.A.J., K.K.S., N.W.); Pharmazentrum Frankfurt/ZAFES, Clinical Pharmacology (N.F.B., G.G.) and Centre for Molecular Medicine, Medical Faculty (N.W.), J.W. Goethe University Frankfurt, Frankfurt, Germany; and Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (C.J.B.).
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.affiliation: From the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.G., D.T., K.T., J.A.J., K.K.S., N.W.); Pharmazentrum Frankfurt/ZAFES, Clinical Pharmacology (N.F.B., G.G.) and Centre for Molecular Medicine, Medical Faculty (N.W.), J.W. Goethe University Frankfurt, Frankfurt, Germany; and Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (C.J.B.). Nina.Wettschureck@mpi-bn.mpg.de.
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019898:Autocrine Communication; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000081025:Sphingosine-1-Phosphate Receptors; D014158:Transcription, Genetic; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D018836:Inflammation Mediators; D016328:NF-kappa B; D011973:Receptors, LDL; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; D044365:GTP-Binding Protein alpha Subunits, G12-G13; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: GTP-binding proteins; atherosclerosis; gene expression; macrophages; signal transduction