title: Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism.
abstract: Microglia become activated immune cells during infection or disease in the central nervous system (CNS). However, the mechanisms that downregulate activated microglia to prevent immune-mediated damage are not completely understood. Vitamin D3 has been suggested to have immunomodulatory affects, and high levels of vitamin D3 have been correlated with a decreased risk for developing some neurological diseases. Recent studies have demonstrated the synthesis of active vitamin D3, 1,25-dihydroxyvitamin D3, within the CNS, but its cellular source and neuroprotective actions remain unknown. Therefore, we wanted to determine whether microglia can respond to vitamin D3 and whether vitamin D3 alters immune activation of microglia. We have previously shown that microglia become activated by IFNγ or LPS or by infection with virus to express pro-inflammatory cytokines, chemokines, and effector molecules. In this study, activated microglia increased the expression of the vitamin D receptor and Cyp27b1, which encodes the enzyme for converting vitamin D3 into its active form, thereby enhancing their responsiveness to vitamin D3. Most importantly, the activated microglia exposed to vitamin D3 had reduced expression of pro-inflammatory cytokines, IL-6, IL-12, and TNFα, and increased expression of IL-10. The reduction in pro-inflammatory cytokines was dependent on IL-10 induction of suppressor of cytokine signaling-3 (SOCS3). Therefore, vitamin D3 increases the expression of IL-10 creating a feedback loop via SOCS3 that downregulates the pro-inflammatory immune response by activated microglia which would likewise prevent immune mediated damage in the CNS.
authors.affiliation: Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, United States.
authors.forename: Mandy
authors.initials: M
authors.lastname: Boontanrart
authors.affiliation: Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, United States.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Hall
authors.affiliation: Department of Medicine, Center for Immunology, University of Minnesota, United States.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Spanier
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, United States.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Hayes
authors.affiliation: Department of Diagnostic and Biological Sciences, University of Minnesota, United States. Electronic address: jkolson@umn.edu.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Olson
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology*; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000276:immunology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10; D002762:Cholecalciferol; D007371:Interferon-gamma; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
keywords: Cytokines; Microglia; Neurological diseases; SOCS3; Virus; Vitamin D