Lee Priscilla W, Selhorst Amanda, Lampe Sara Gombash, Liu Yue, Yang Yuhong, Lovett-Racke Amy E
Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Front Neurol. 2020 Jan 31;11:19. doi: 10.3389/fneur.2020.00019. eCollection 2020.
Low vitamin D during childhood is associated with an increased risk of developing multiple sclerosis (MS) as an adult. Given that vitamin D has anti-inflammatory properties, it has been postulated that the relationship between MS and low vitamin D is due to immune dysregulation. Since the vitamin D receptor (VDR) is expressed in many cell types, this study investigated an alternative hypothesis-neuron-specific VDR signaling induces anti-inflammatory molecules that protect the central nervous system from autoimmunity. Using media from neurons treated with calcitriol, the active form of vitamin D, LPS-activated microglia had a reduction in pro-inflammatory molecules, and a reciprocal induction of anti-inflammatory molecules. Since IL-34 is critical to the homeostasis of microglia, and was previously shown to be induced in endothelial cells by vitamin D, we investigated IL-34 as the potential anti-inflammatory molecule induced in neurons by vitamin D. Treatment of LPS-activated microglia with IL-34 reduced pro-inflammatory cytokine production and enhanced the expression of anti-inflammatory transcripts. However, neutralizing IL-34 in vitamin D neuronal conditioned media only impacted IL-6 and not the broader anti-inflammatory phenotype of microglia. To mimic low vitamin D in children, we used a neuron-specific inducible mouse model in which VDR was partially deleted in juvenile mice. Partial deletion of VDR in neurons during early life resulted in exacerbated CNS autoimmunity in adult mice. Overall, the study illustrated that vitamin D signaling in neurons promotes an anti-inflammatory state in microglia, and low vitamin D in early life may enhance CNS autoimmunity.
儿童时期维生素D水平低与成年后患多发性硬化症（MS）的风险增加有关。鉴于维生素D具有抗炎特性，有人推测MS与低维生素D之间的关系是由于免疫失调。由于维生素D受体（VDR）在多种细胞类型中表达，本研究调查了另一种假设——神经元特异性VDR信号传导诱导抗炎分子，从而保护中枢神经系统免受自身免疫的影响。使用来自用骨化三醇（维生素D的活性形式）处理的神经元的培养基，脂多糖激活的小胶质细胞中促炎分子减少，抗炎分子相互诱导。由于IL-34对小胶质细胞的稳态至关重要，并且先前已证明它在维生素D作用下在内皮细胞中被诱导，我们研究了IL-34作为维生素D在神经元中诱导的潜在抗炎分子。用IL-34处理脂多糖激活的小胶质细胞可减少促炎细胞因子的产生，并增强抗炎转录本的表达。然而，在维生素D神经元条件培养基中中和IL-34仅影响IL-6，而不影响小胶质细胞更广泛的抗炎表型。为了模拟儿童低维生素D的情况，我们使用了一种神经元特异性诱导小鼠模型，其中VDR在幼年小鼠中被部分缺失。生命早期神经元中VDR的部分缺失导致成年小鼠中枢神经系统自身免疫加剧。总体而言，该研究表明神经元中的维生素D信号传导促进小胶质细胞的抗炎状态，生命早期低维生素D可能会增强中枢神经系统自身免疫。
