The Vitamin D-Gelsolin-S1P Axis in Rheumatoid Arthritis

类风湿关节炎中的维生素 D-凝溶胶蛋白-S1P 轴

• 批准号: 9412753
• 负责人: ARNOLD E POSTLETHWAITE
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412753
• 关键词: Acute; Adjuvant Arthritis; Affect; Age; Alzheimer' s Disease; Anti-citrullinated peptide antibody; Arthritis; Attention; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Binding; Burn injury; C-reactive protein; CD4 Positive T Lymphocytes; Cells; Cholecalciferol; Chronic; Clinical; Clinical assessments; Collagen Type II; Collagen-Induced Arthritis; Confounding Factors (Epidemiology); Data; Dendritic Cells; Diet; Disease; Dose; Encephalitis; Ethnic Origin; FOXP3 gene; Febrile Convulsions; G-Protein-Coupled Receptors; Gelsolin; Gender; Heart Diseases; Human; IL2RA gene; Immune response; In Vitro; Individual; Inflammatory Arthritis; Inflammatory Response; Linear Regressions; Literature; Liver diseases; Lung diseases; Lymphocyte; Lymphoid Tissue; Malaria; Malignant Neoplasms; Measurement; Measures; Messenger RNA; Metabolism; Modeling; Mus; Myoblasts; Normal Range; Operative Surgical Procedures; Outcome; Patients; Peripheral Blood Mononuclear Cell; Pilot Projects; Plasma; Pneumonia; Population; Production; Race; Rattus; Regulatory T-Lymphocyte; Renal dialysis; Replacement Therapy; Reporting; Rheumatoid Arthritis; Risk; Rodent Model; Serum; Skeletal Muscle; Spearman Rank Correlation Coefficient; Sphingosine-1-Phosphate Receptor; Splenocyte; Stroke; Synovial Fluid; T-Lymphocyte; TNF gene; Testing; Time; Transgenic Mice; Trauma; Veterans; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; analog; base; cytokine; healthy volunteer; immune function; improved; knock-down; macrophage; monocyte; mortality; mouse model; novel; peripheral blood; predictive modeling; response; sphingosine 1-phosphate; sphingosine kinase; trafficking

Vitamin D deficiency (VitD-) is commonly encountered in patients with rheumatoid arthritis (RA) (and other autoimmune diseases). Some studies show VitD levels impact expression of RA, but the mechanism(s) have not been well explored and have received scant attention in rodent models of RA. Interestingly, like VitD levels, in studies looking at only plasma gelsolin (pGSN), it was observed that pGSN levels also inversely correlate with C-reactive protein (CRP) in patients with RA. Gelsolin (GSN) has been shown to be protective in the TNFα transgenic (tg) mouse model of RA. It is known that sphingosine 1-phosphate (S1P) (acting through G protein- coupled receptors on T cells, B cells, monocytes/macrophages, and dendritic cells) affect immune and inflammatory responses and has been found to be elevated in RA synovial fluid but not osteoarthritis synovial fluid. Furthermore, pGSN binds to S1P, thereby regulating its ability to engage S1P receptors. We found humans, in addition to converting vitamin D3 (VitD3) to 25(OH)D3, also generate a noncalcemic analog, 20(OH)D3, with a serum concentration 1/20th of that of 25(OH)D3. In the type II collagen-induced arthritis (CIA), we found surprisingly that 20(OH)D3 treatment elevates pGSN levels and increases S1P levels in splenocyte cultures from these 20(OH)D3-treated mice. We discovered that supplementing VitD in humans elevates pGSN in sera and that 25(OH)D levels in normals and in RA and OA correlate fairly well with pGSN. Also, we found both 20(OH)D3 and 1,25(OH)2D3 increased sphingosine kinase (Sphk)2 mRNA in mouse splenocytes and increased GSN mRNA in cultured mouse myoblasts and pGSN production by explant cultures of mouse skeletal muscle. Knocking down GSN or Sphk2 worsens arthritis in mouse models of RA. Both GSN and Sphk2 regulate S1P levels in plasma or lymphoid tissue, which is important in immune function, including lymphocyte trafficking, Th1/Th2/Th17 cytokine expression, and control of FoxP3 regulatory T cells (Tregs). No studies have evaluated levels of 25(OH)D, S1P, and pGSN in the same RA population. We find 25(OH)D serum levels correlate fairly well with pGSN levels in RA patients, although concordance is not 100%. We further hypothesize that RA patients who have both high 25(OH)D and pGSN will have less RA disease activity score, while those with low pGSN and low 25(OH)D will have higher RA disease activity scores. Our overarching hypothesis is that there are interactions amongst VitD, GSN, and CD4+ T cell Sphk2, CD4+ T cell S1P receptor subtypes, and/or S1P that may be important in the modulation of autoimmunity and inflammatory arthritis. Whether administering VitD to humans with VitD deficiency/insufficiency will raise pGSN levels and modulate S1P, is unknown, and is the topic of Specific Aim 3. The three highly translational Specific Aims of this proposal are the following: Specific Aim 1A: Assess the association of serum levels of 25(OH)D, pGSN, and S1P separately, in patients with RA with measures of RA disease activity. Specific Aim 1B: Assess whether a clinical prediction model or models containing serum 25(OH)D, pGSN, and/or S1P levels provide more reliable prediction of the selected markers or measurements of RA disease activity than any single predictor alone. Specific Aim 2: To test the hypothesis that VitD replacement therapy in humans with OA or RA with VitD- will elevate levels of pGSN, reduce levels of S1P in plasma, and change lymphocyte expression of Sphk2. Specific Aim 3: To test the hypothesis that high dose VitD replacement therapy in patients with OA or RA and VitD- will reduce Th1, Th9, and Th17 effector T cells, increase Th2 and CD4+Tregs in peripheral blood, and whether there is interaction with existing plasma levels of pGSN and S1P. We also found that serum 25(OH)D levels correlate with pGSN in patients with RA and (in a small pilot study) that VitD supplementation in humans [healthy volunteers (HV) and patients with RA] raised 25(OH)D levels from insufficiency to normal range and was also associated with increases in pGSN. This suggests that (in both mice and humans) pGSN is partially regulated by VitD.

维生素 D 缺乏症 (VitD-) 常见于类风湿性关节炎 (RA)（以及其他疾病）患者。 自身免疫性疾病）。一些研究表明 VitD 水平影响 RA 的表达，但其机制 尚未得到很好的探索，并且在 RA 啮齿动物模型中也很少受到关注。有趣的是，就像维生素D水平一样， 在仅关注血浆凝溶胶蛋白 (pGSN) 的研究中，观察到 pGSN 水平也呈负相关 RA 患者的 C 反应蛋白（CRP）。凝溶胶蛋白 (GSN) 已被证明对 TNFα 具有保护作用 RA 转基因 (tg) 小鼠模型。众所周知，1-磷酸鞘氨醇 (S1P)（通过 G 蛋白发挥作用） T 细胞、B 细胞、单核细胞/巨噬细胞和树突状细胞上的偶联受体）影响免疫和 炎症反应，并且已发现在 RA 滑液中升高，但在骨关节炎滑液中不升高 体液。此外，pGSN 与 S1P 结合，从而调节其与 S1P 受体结合的能力。我们发现 人类除了将维生素 D3 (VitD3) 转化为 25(OH)D3 之外，还产生一种非钙血症类似物， 20(OH)D3，血清浓度是25(OH)D3的1/20。在 II 型胶原诱导的关节炎中 (CIA)，我们令人惊讶地发现 20(OH)D3 治疗可提高 pGSN 水平并增加 S1P 水平 来自这些 20(OH)D3 处理小鼠的脾细胞培养物。我们发现补充人类维生素D 升高血清中的 pGSN，并且正常人以及 RA 和 OA 中的 25(OH)D 水平与 pGSN 相关性相当好。 此外，我们还发现 20(OH)D3 和 1,25(OH)2D3 都能增加小鼠中的鞘氨醇激酶 (Sphk)2 mRNA 脾细胞和培养的小鼠成肌细胞中 GSN mRNA 的增加以及外植体培养物中 pGSN 的产生 小鼠骨骼肌。在 RA 小鼠模型中，敲低 GSN 或 Sphk2 会使关节炎恶化。两者都是GSN Sphk2 调节血浆或淋巴组织中的 S1P 水平，这对免疫功能很重要，包括 淋巴细胞运输、Th1/Th2/Th17 细胞因子表达以及 FoxP3 调节性 T 细胞 (Treg) 的控制。不 研究评估了同一 RA 人群中 25(OH)D、S1P 和 pGSN 的水平。我们发现 25(OH)D RA 患者的血清水平与 pGSN 水平相关性相当好，尽管一致性不是 100%。我们 进一步假设 25(OH)D 和 pGSN 均较高的 RA 患者的 RA 疾病活动性较低 评分，而 pGSN 和 25(OH)D 较低的患者将具有较高的 RA 疾病活动评分。我们的 总体假设是 VitD、GSN 和 CD4+ T 细胞 Sphk2、CD4+ 之间存在相互作用 T 细胞 S1P 受体亚型和/或 S1P 在调节自身免疫和 炎症性关节炎。对 VitD 缺乏/不足的人施用 VitD 是否会提高 pGSN 水平和调节 S1P 尚不清楚，并且是特定目标 3 的主题。这三个高度转化的 该提案的具体目标如下： 具体目标 1A：评估血清水平的关联 分别测量 RA 患者的 25(OH)D、pGSN 和 S1P，并测量 RA 疾病活动度。 具体目标 1B：评估临床预测模型或模型是否含有血清 25(OH)D、 pGSN 和/或 S1P 水平提供了对所选标记或测量的更可靠的预测 RA 疾病的活性高于任何单一预测因子​​。具体目标 2：检验 VitD 的假设 用 VitD 替代治疗 OA 或 RA 患者会提高 pGSN 水平，降低 血浆中的S1P，并改变淋巴细胞Sphk2的表达。具体目标 3：检验假设 OA 或 RA 患者的高剂量 VitD 替代疗法和 VitD- 将减少 Th1、Th9 和 Th17效应T细胞，外周血中Th2和CD4+Tregs增加，是否存在相互作用 与现有的血浆 pGSN 和 S1P 水平。我们还发现血清 25(OH)D 水平与 RA 患者中的 pGSN 以及（在一项小型试点研究中）人类 [健康志愿者] 中补充 VitD (HV) 和 RA 患者] 将 25(OH)D 水平从不足升高至正常范围，并且也相关 随着 pGSN 的增加。这表明（在小鼠和人类中）pGSN 部分受 VitD 调节。