All-Trans-Retinoic Acid Augments the Histopathological Outcome of Neuroinflammation and Neurodegeneration in Lupus-Prone MRL/lpr Mice

Abstract

Recently, we demonstrated that treatment with all- trans-retinoic acid (tRA) induced a paradoxical effect on immune activation during the development of autoimmune lupus. Here, we further describe its negative effects on mediating neuroinflammation and neurodegeneration. Female MRL/lpr mice were orally administered tRA or VARA (retinol mixed with 10% tRA) from 6 to 14 weeks of age. Both treatments had a significant effect on brain weight, which correlated with histopathological evidence of focal astrogliosis, meningitis, and ventriculitis. Infiltration of CD138- and Iba1-positve immune cells was observed in the third ventricle and meninges of treated mice that co-labeled with ICAM-1, indicating their inflammatory nature. Increased numbers of circulating plasma cells, autoantibodies, and total IgG were also apparent. IgG and C3 complement deposition in these brain regions were also prominent as was focal astrogliosis surrounding the ventricular lining and meninges. Using Fluoro-Jade staining, we further demonstrate that neuroinflammation was accompanied by neurodegeneration in the cortex of treated mice compared with vehicle controls. These findings indicate that vitamin A exposure exacerbates the immunogenic environment of the brain during the onset of systemic autoimmune disease. Vitamin A may therefore compromise the immuno-privileged nature of the central nervous system under a predisposed immunogenic environment.

Retinoic Acid, Leaky Gut, and Autoimmune Diseases

“…For instance, supplementation of RA can ameliorate some tissues’ pathologies, as in the kidney during lupus nephritis, while deteriorating other tissue pathologies, for instance, the lung and skin lesions [ 82 ]. Similarly, RA treatment exacerbates neuroinflammation by increasing autoantibodies, total IgG, and complement C3 protein deposition in the brain tissue and has been associated with more severe neurodegeneration in MRL/lpr mice [ 83 ]. Furthermore, with its potential toxicity [ 84 , 85 ], employing RA as a potential therapeutic for autoimmune disorders requires a deeper consideration for the context in which RA interplays.…”

Administration of all‐transretinoic acid after experimental traumatic brain injury is brain protective

“…Interestingly, pre‐injury administration of ATRA reduced infarction volume after experimental stroke and improved neurological outcome and integrity of the BBB (Li et al, 2017, 2018). To some degree, the beneficial effects of ATRA have been attributed to its anti‐inflammatory actions (Behairi et al, 2016; Choi et al, 2009; Theus, Sparks, Liao, Ren, & Luo, 2017). Indeed, several in vitro studies showed that ATRA suppressed inflammatory responses of microglia and astrocytes (Dheen, Jun, Yan, Tay, & Ling, 2005; van Neerven et al, 2010; Xu & Drew, 2006).…”

Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus

“…Progressive Glomerulonephritis With tRA Pre-treatment in Pristane-Induced Lupus tRA treatment of lupus-prone MRL/lpr mice showed paradoxical effects on renal inflammation vs. other tissue pathologies including inflammation of the skin, lungs 12, and neuroinflammation (13), suggesting that tRA can expand the pre-existing immunogenic environment in extrarenal organs in genetically prone lupus. In this study, we further hypothesized that the effects of tRA on lupus disease were disease stage-dependent.…”

“…Even though retinoid treatment in combination with immunosuppressive drugs showed beneficial effects on lupus nephritis (11), previous findings from our group showed that tRA has paradoxical implications on renal inflammation vs. other tissue pathologies. tRA supplementation during active disease aggravated pathologies in non-renal tissues including skin, lungs (12), and brain (13). These findings indicate that tRA may act as an adjuvant to exacerbate the pre-existing, extrarenal inflammation in individuals genetically prone to develop lupus.…”