Treatment with 1,25-Dihydroxyvitamin D3 Delays Choroid Plexus Infiltration and BCSFB Injury in MRL/lpr Mice Coinciding with Activation of the PPARγ/NF-κB/TNF-α Pathway and Suppression of TGF-β/Smad Signaling

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication of systemic lupus erythematosus (SLE) involving the nervous system with high morbidity and mortality. A key hypothesis in NPSLE is that a disrupted barrier allows autoantibodies and immune components of peripheral blood to penetrate into the central nervous system (CNS), resulting in inflammation and damage. The blood cerebrospinal fluid barrier (BCSFB), which consists of the choroid plexus and the hypothalamic tanycytes, has long been regarded as an immunological sanctuary site. 1,25-Dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] is the active form of vitamin D, which plays multiple roles in inflammation and immunoregulation. In this study, we investigated the possible protective effects of 1,25-dihydroxyvitamin D-3 against BCSFB dysfunction in NPSLE in MRL/lpr mice and explored the mechanism by which 1,25-dihydroxyvitamin D-3 inhibits the progression of NPSLE. In this study, we found that supplementation with 1,25-dihydroxyvitamin D-3 markedly improved serological and immunological indices, delayed inflammatory infiltration, delayed neuronal deformation, and upregulated the expression of brain-derived neurotrophic factor (BDNF) proteins in the brain. Furthermore, 1,25-dihydroxyvitamin D-3 downregulated proinflammatory cytokines such as nuclear factor kappa-B (NF-kappa B) and tumor necrosis factor-alpha (TNF-alpha) by activating peroxisome proliferator-activated receptor gamma (PPAR gamma), and it reduced the expression of the TGF-beta/Smad signaling pathway. Our findings demonstrate that 1,25-dihydroxyvitamin D-3 delayed cell infiltration into the choroid plexus and decreased markers suggestive of cognitive decline in MRL/lpr mice, and the mechanism may be related to protection against BCSFB disruption through activation of the anti-inflammatory PPAR gamma/NF-kappa B/TNF-alpha pathway as well as upregulation of BDNF and inhibition of the TGF-beta/Smad signaling pathway. These findings provide a novel direction for the study of NPSLE.