1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking.
Multiple sclerosis (MS) is a complex neurodegenerative disease whose pathogenesis involves genetic and environmental risk factors leading to an aberrant, neuroantigen-specific, CD4+ T cell-mediated autoimmune response. In support of the hypothesis that vitamin D3 may reduce MS risk and severity, we found that vitamin D3 and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) inhibited induction of experimental autoimmune encephalomyelitis (EAE), an MS model. To investigate how 1,25-(OH)2D3 could carry out anti-inflammatory functions, we administered 1,25-(OH)2D3 or a placebo to mice with EAE, and subsequently analyzed clinical disease, chemokines, inducible nitric oxide synthase (iNOS), and recruitment of dye-labeled monocytes. The 1,25-(OH)2D3 treatment significantly reduced clinical EAE severity within 3 days. Sharp declines in chemokines, inducible iNOS, and CD11b+ monocyte recruitment into the central nervous system (CNS) preceded this clinical disease abatement in the 1,25-(OH)2D3-treated animals. The 1,25-(OH)2D3 did not directly and rapidly inhibit chemokine synthesis in vivo or in vitro. Rather, the 1,25-(OH)2D3 rapidly stimulated activated CD4+ T cell apoptosis in the CNS and spleen. Collectively, these results support a model wherein inflammation stimulates a natural anti-inflammatory feedback loop. The activated inflammatory cells produce 1,25-(OH)2D3, and this hormone subsequently enhances the apoptotic death of inflammatory CD4+ T cells, removing the driving force for continued inflammation. In this way, the sunlight-derived hormone could reduce the risk of chronic CNS inflammation and autoimmune-mediated neurodegenerative disease.
Pedersen
Laura B
LB
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Nashold
Faye E
FE
Spach
Karen M
KM
Hayes
Colleen E
CE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002117:Calcitriol / Q000494:pharmacology*; D018925:Chemokines / Q000096:biosynthesis*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D007150:Immunohistochemistry; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D014815:Vitamins / Q000494:pharmacology
D018925:Chemokines; D018696:Neuroprotective Agents; D014815:Vitamins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D002117:Calcitriol