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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

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Abstract

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 D3 [1,25-(OH)2D3] 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 D3 against BCSFB dysfunction in NPSLE in MRL/lpr mice and explored the mechanism by which 1,25-dihydroxyvitamin D3 inhibits the progression of NPSLE. In this study, we found that supplementation with 1,25-dihydroxyvitamin D3 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 D3 downregulated proinflammatory cytokines such as nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) by activating peroxisome proliferator-activated receptor γ (PPARγ), and it reduced the expression of the TGF-β/Smad signaling pathway. Our findings demonstrate that 1,25-dihydroxyvitamin D3 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 PPARγ/NF-κB/TNF-α pathway as well as upregulation of BDNF and inhibition of the TGF-β/Smad signaling pathway. These findings provide a novel direction for the study of NPSLE.

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DATA AVAILABILITY

The datasets during the current study are available from the corresponding author on reasonable request.

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ACKNOWLEDGEMENTS

We thank Dr. Yanqiang Wang for his instructive advice and useful suggestions on my thesis, and providing to help experiment design and completion in the study.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81870943).

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Authors and Affiliations

  1. Department of Rheumatology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China

    Xuewei Li

  2. Department of Neurology II, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China

    Shuangli Xu, Yingzhe Zhao & Yanqiang Wang

  3. Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China

    Jie Liu & Xiangling Li

  4. Department of Anesthesiology, Weifang Medical University, Weifang, Shandong, China

    Huirong Han

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Contributions

This article is mainly written by XWL and SX. JL and YZ wrote part of the manuscript and proofread the manuscript. RH helped us collect literature information and draw pictures. XLL and YW reviewed the manuscript and proposed final revisions. All authors contributed to the article and approved the submitted version.

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Correspondence to Xiangling Li or Yanqiang Wang.

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All experiments were performed according to the institutional ethical guidelines on animal care and approved by the Institute Animal Care and Use Committee at the Weifang Medical University, Shandong, China.

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Li, X., Xu, S., Liu, J. et al. 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. Inflammation 46, 556–572 (2023). https://doi.org/10.1007/s10753-022-01755-5

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