title: Regulator of G Protein Signaling 10 (Rgs10) Expression Is Transcriptionally Silenced in Activated Microglia by Histone Deacetylase Activity.
abstract: RGS10 has emerged as a key regulator of proinflammatory cytokine production in microglia, functioning as an important neuroprotective factor. Although RGS10 is normally expressed in microglia at high levels, expression is silenced in vitro following activation of TLR4 receptor. Given the ability of RGS10 to regulate inflammatory signaling, dynamic regulation of RGS10 levels in microglia may be an important mechanism to tune inflammatory responses. The goals of the current study were to confirm that RGS10 is suppressed in an in vivo inflammatory model of microglial activation and to determine the mechanism for activation-dependent silencing of Rgs10 expression in microglia. We demonstrate that endogenous RGS10 is present in spinal cord microglia, and RGS10 protein levels are suppressed in the spinal cord in a nerve injury-induced neuropathic pain mouse model. We show that the histone deacetylase (HDAC) enzyme inhibitor trichostatin A blocks the ability of lipopolysaccharide (LPS) to suppress Rgs10 transcription in BV-2 and primary microglia, demonstrating that HDAC enzymes are required for LPS silencing of Rgs10 Furthermore, we used chromatin immunoprecipitation to demonstrate that H3 histones at the Rgs10 proximal promoter are deacetylated in BV-2 microglia following LPS activation, and HDAC1 association at the Rgs10 promoter is enhanced following LPS stimulation. Finally, we have shown that sphingosine 1-phosphate, an endogenous microglial signaling mediator that inhibits HDAC activity, enhances basal Rgs10 expression in BV-2 microglia, suggesting that Rgs10 expression is dynamically regulated in microglia in response to multiple signals.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia (M.A., M.W.A., R.Y., M.G., H.-R.W., S.B.H.); and Department of Biology, Georgia State University, Atlanta, Georgia (N.M., E.C., S.F.G.).
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alqinyah
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia (M.A., M.W.A., R.Y., M.G., H.-R.W., S.B.H.); and Department of Biology, Georgia State University, Atlanta, Georgia (N.M., E.C., S.F.G.).
authors.forename: Nagini
authors.initials: N
authors.lastname: Maganti
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia (M.A., M.W.A., R.Y., M.G., H.-R.W., S.B.H.); and Department of Biology, Georgia State University, Atlanta, Georgia (N.M., E.C., S.F.G.).
authors.forename: Mourad W
authors.initials: MW
authors.lastname: Ali
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia (M.A., M.W.A., R.Y., M.G., H.-R.W., S.B.H.); and Department of Biology, Georgia State University, Atlanta, Georgia (N.M., E.C., S.F.G.).
authors.forename: Ruchi
authors.initials: R
authors.lastname: Yadav
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia (M.A., M.W.A., R.Y., M.G., H.-R.W., S.B.H.); and Department of Biology, Georgia State University, Atlanta, Georgia (N.M., E.C., S.F.G.).
authors.forename: Mei
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia (M.A., M.W.A., R.Y., M.G., H.-R.W., S.B.H.); and Department of Biology, Georgia State University, Atlanta, Georgia (N.M., E.C., S.F.G.).
authors.forename: Ercan
authors.initials: E
authors.lastname: Cacan
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia (M.A., M.W.A., R.Y., M.G., H.-R.W., S.B.H.); and Department of Biology, Georgia State University, Atlanta, Georgia (N.M., E.C., S.F.G.).
authors.forename: Han-Rong
authors.initials: HR
authors.lastname: Weng
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia (M.A., M.W.A., R.Y., M.G., H.-R.W., S.B.H.); and Department of Biology, Georgia State University, Atlanta, Georgia (N.M., E.C., S.F.G.).
authors.forename: Susanna F
authors.initials: SF
authors.lastname: Greer
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia (M.A., M.W.A., R.Y., M.G., H.-R.W., S.B.H.); and Department of Biology, Georgia State University, Atlanta, Georgia (N.M., E.C., S.F.G.) shooks@uga.edu.
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Hooks
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D002460:Cell Line; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D020868:Gene Silencing / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D008780:Methyltransferases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D020710:RGS Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C491068:Rgs10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C060506:sphingosine 1-phosphate; C012589:trichostatin A; D008780:Methyltransferases; D006655:Histone Deacetylases; D001374:Azacitidine; D013110:Sphingosine