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-）通常发生在类风湿性关节炎（RA）患者（以及其他 自身免疫性疾病）。一些研究表明，维生素D水平影响RA的表达，但其机制有 在RA的啮齿动物模型中尚未得到充分研究，也很少受到关注。有趣的是，像维生素D水平， 在仅观察血浆凝溶胶蛋白（pGSN）的研究中，观察到pGSN水平也与血浆凝溶胶蛋白（pGSN）水平负相关。 与C反应蛋白（CRP）的关系。凝溶胶蛋白（GSN）已被证明是保护性的TNFα RA的转基因（tg）小鼠模型。已知1-磷酸鞘氨醇（S1 P）（通过G蛋白- T细胞、B细胞、单核细胞/巨噬细胞和树突细胞上的偶联受体）影响免疫和 在RA滑液中升高，但在骨关节炎滑液中不升高。 液此外，pGSN与S1 P结合，从而调节其接合S1 P受体的能力。我们发现 人类除了将维生素D3（VitD 3）转化为25（OH）D3外，还产生非钙离子类似物， 20（OH）D3，血清浓度为25（OH）D3的1/20。在II型胶原诱导的关节炎中， (CIA)我们惊奇地发现，20（OH）D3处理提高了pGSN水平，并增加了S1 P水平。 来自这些20只（OH）D3处理的小鼠的脾细胞培养物。我们发现补充维生素D 升高血清中的pGSN，并且正常人和RA及OA中的25（OH）D水平与pGSN相当好地相关。 20（OH）D_3和1，25（OH）_2D_3均能增加小鼠神经鞘氨醇激酶（Sphk）_2 mRNA的表达 脾细胞和增加的GSN mRNA在培养的小鼠成肌细胞和pGSN生产外植体培养 小鼠的骨骼肌。在RA小鼠模型中敲除GSN或Sphk 2抑制关节炎。两个GSN 和Sphk 2调节血浆或淋巴组织中的S1 P水平，其在免疫功能中是重要的，包括 淋巴细胞运输、Th 1/Th 2/Th 17细胞因子表达和FoxP 3调节性T细胞（TCFs）的控制。没有 研究已经评估了相同RA人群中25（OH）D、S1 P和pGSN的水平。我们发现25（OH）D 在RA患者中，血清水平与pGSN水平相关性相当好，尽管一致性不是100%。我们 进一步假设同时具有高25（OH）D和pGSN的RA患者将具有较少的RA疾病活动性 低pGSN和低25（OH）D的患者将具有较高的RA疾病活动性评分。我们 总体假设是VitD、GSN和CD 4 + T细胞Sphk 2、CD 4 + T细胞Sphk 2和CD 4 + T细胞Sphk 3之间存在相互作用。 T细胞S1 P受体亚型，和/或可能在自身免疫调节中重要的S1 P， 炎性关节炎对维生素D缺乏/不足的人给予维生素D是否会提高 pGSN水平和调节S1 P，是未知的，是具体目标3的主题。三个高度翻译 本提案的具体目标如下：具体目标1A：评估血清水平 25（OH）D，pGSN，和S1 P分别在RA患者与RA疾病活动的措施。 具体目标1B：评估临床预测模型或含有血清25（OH）D的模型， pGSN和/或S1 P水平提供了对所选标志物的更可靠的预测或 RA疾病活动度比任何单一预测因子都高。具体目标2：检验维生素D 在患有OA或RA的人中使用VitD的替代疗法-将升高pGSN水平，降低 S1 P的表达，并改变淋巴细胞Sphk 2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-将降低Th 1，Th 9， Th 17效应T细胞，增加外周血中Th 2和CD 4 + T细胞，以及是否存在相互作用 pGSN和S1 P的血浆水平。我们还发现，血清25（OH）D水平与 在RA患者中的pGSN和（在一项小型试点研究中）在人类[健康志愿者]中补充VitD (HV)和RA患者] 25（OH）D水平从不足升高到正常范围， 随着pGSN的增加。这表明（在小鼠和人类中）pGSN部分受VitD调节。