Calcitriol Prevents Neuroinflammation and Reduces Blood-Brain Barrier Disruption and Local Macrophage/Microglia Activation.

Larissa Ragozo Cardoso De Oliveira,Alexandrina Sartori,Luiza Ayumi Nishiyama Mimura,Sofia Fernanda Gonçalves Zorzella-Pezavento,Thais Fernanda De Campos Fraga-Silva,Larissa Lumi Watanabe Ishikawa,Ana Angélica Henrique Fernandes

doi:10.3389/fphar.2020.00161

Larissa Ragozo Cardoso De Oliveira, Alexandrina Sartori + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2020.00161

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Abstract

Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that involves damage to the myelin sheath surrounding axons. MS therapy is based on immunomodulatory drugs that reduce disease recurrence and severity. Vitamin D is a hormone whose immunomodulatory ability has been widely demonstrated, including in experimental autoimmune encephalomyelitis (EAE), which is an animal model of CNS inflammation. In this study, we evaluated the potential of very early intervention with the active form of vitamin D (1,25-dihydroxyvitamin D3) to control neuroinflammation during EAE development. EAE was induced in C57BL/6J mice and 1,25-dihydroxyvitamin D3 administration began 1 day after disease induction. This procedure decreased prevalence, clinical score, inflammation, and demyelination. It also reduced MHCII expression in macrophages and microglia as well as the level of oxidative stress and messenger RNA (mRNA) expression for NLRP3, caspase-1, interleukin (IL)-1β, CX3CR1, CCL17, RORc and Tbx21 at the CNS. Otherwise, mRNA expression for ZO-1 increased at the lumbar spinal cord. These effects were accompanied by the stabilization of blood-spinal cord barrier permeability. The results of this study indicate that early intervention with 1,25-dihydroxyvitamin D3 can control the neuroinflammatory process that is the hallmark of EAE and MS immunopathogenesis and should thus be explored as an adjunct therapy for MS patients.

Highlights

Multiple sclerosis (MS) has been classically categorized as an autoimmune disease in which self-reactive T CD4+ (Th1/Th17), T CD8+, and B cells attack the central nervous system (CNS) and cause neurological dysfunction (Yadav et al, 2015)
We evaluated the potential of very early intervention with the active form of vitamin D (1,25-dihydroxyvitamin D3) to control neuroinflammation during EAE development
The results of this study indicate that early intervention with 1,25-dihydroxyvitamin D3 can control the neuroinflammatory process that is the hallmark of EAE and MS immunopathogenesis and should be explored as an adjunct therapy for MS patients

Summary

Introduction

Multiple sclerosis (MS) has been classically categorized as an autoimmune disease in which self-reactive T CD4+ (Th1/Th17), T CD8+, and B cells attack the central nervous system (CNS) and cause neurological dysfunction (Yadav et al, 2015). It has been postulated that MS starts when self-reactive T cells are activated by autoantigen recognition in peripheral lymphoid organs. Once in the CNS, these cells recognize self-antigens at the surface of antigen-presenting cells (APCs), undergo activation and proliferation, and release a plethora of proinflammatory mediators (Garg and Smith, 2015). Cells from innate and specific immunity trigger an inflammatory process that culminates in demyelination and axonal loss (Hemme et al, 2015). Increasing evidence indicates that oxidative stress and inflammasome activation serve a major role in demyelination and axonal damage (Ohl et al, 2016; Barclay and Shinohara, 2017)

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