Interference with RhoA-ROCK signaling mechanism in autoreactive CD4+ T cells enhances the bioavailability of 1,25-dihydroxyvitamin D3 in experimental autoimmune encephalomyelitis.
Vitamin D deficiency is a major risk factor for central nervous system (CNS) demyelinating diseases including multiple sclerosis (MS) and its animal model, that of experimental autoimmune encephalomyelitis (EAE). Both vitamin D(3) and 1, 25-dihydroxyviatmin-D(3) (calcitriol) had beneficial effects in EAE/MS. However, the exact cause of vitamin D deficiency in EAE/MS is not clear. Previously, we documented that lovastatin (LOV) provides protection in EAE animals via inhibition of RhoA-ROCK signaling. Herein, we demonstrate that LOV prevents the lowering of circulating 25-hydroxyvitamin-D(3) and 1,25-dihydroxyviatmin-D(3) levels including 1,25-dihydroxyviatmin-D(3) levels in the peripheral lymphoid organs and CNS of treated EAE animals. These effects of LOV were attributed to enhanced expression of vitamin D synthesizing enzyme (1α-hydroxylase) in kidney and the CNS, with corresponding reduction of vitamin D catabolizing enzyme (24-hydorxylase) expression in the CNS of EAE animals via inhibition of RhoA-ROCK signaling. Ex vivo and in vitro studies established that autoreactive Th1/Th17 cells had higher expression of 24-hydroxylase than Th2/T regulatory cells, that was reverted by LOV or ROCK inhibitor. Interestingly, LOV-mediated regulation of vitamin D metabolism had improved vitamin D(3) efficacy to confer protection in EAE animals and that was ascribed to the LOV- and calcitriol-induced immunomodulatory synergy. Together, these data provide evidence that interfering with RhoA-ROCK signaling in autoreactive Th1/Th17 cells can improve vitamin D(3) efficacy in clinical trials of MS and related neurodegenerative disorders.
Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, USA.
Ajaib S
AS
Paintlia
Manjeet K
MK
Paintlia
Bruce W
BW
Hollis
Avtar K
AK
Singh
Inderjit
I
Singh
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D053898:Biosynthetic Pathways / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000382:microbiology*; D002117:Calcitriol / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000201:enzymology* / Q000276:immunology*; D005260:Female; D006168:Guinea Pigs; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000473:pathology; D008148:Lovastatin / Q000494:pharmacology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008798:Mevalonic Acid / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013250:Steroid Hydroxylases / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D065668:Vitamin D3 24-Hydroxylase; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D008148:Lovastatin; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D002117:Calcitriol; D008798:Mevalonic Acid