Canonical and non-canonical vitamin D activation pathways in systemic lupus

系统性狼疮的经典和非经典维生素 D 激活途径

• 批准号: 10247741
• 负责人: Chander Raman
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247741
• 关键词: Address; Affect; Agonist; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biochemical Pathway; Biological; Biological Response Modifiers; Biology; CD8-Positive T-Lymphocytes; CYP11A1 gene; CYP27B1 gene; Calcifediol; Cells; Cholecalciferol; Cholesterol; Complement; Defect; Development; Disease; Enzymes; Fatigue; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Generations; Goals; Hormonal; Hydroxylation; IL17 gene; Immune; Immune response; Immune system; Immunity; Immunologist; Immunology; Innate Immune System; Kidney; Knowledge; Liver; Lupus; Measurement; Measures; Memory; Messenger RNA; Metabolic Pathway; Metabolism; National Institute of Environmental Health Sciences; Pathogenesis; Pathologist; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Pregnenolone; Production; Proteins; Regulation; Regulatory T-Lymphocyte; Repression; Research Personnel; Role; Serum; Severities; Severity of illness; Side; Signal Pathway; Signal Repression; Signal Transduction; Steroid biosynthesis; Supplementation; Systemic Lupus Erythematosus; T cell response; T-Lymphocyte; Testing; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Vitamin D3 Receptor; attenuation; autocrine; base; immunoregulation; liquid chromatography mass spectrometry; monocyte; novel; orphan nuclear receptor ROR-gamma; paracrine; receptor; response; rheumatologist

Project Summary In systemic lupus erythematosus (SLE) the deficiency in vitamin D3 (D3), an essential regulator of immune system, is common and is associated with disease severity and fatigue. However, responses to vitamin D supplementation ranged from some benefit to no benefit even in situations where normal serum levels of 25(OH)D3 (liver vitamin D3 metabolite) was achieved. The underlying mechanism/s for this variable response is unknown and represents a critical gap in our knowledge. This proposal will test a very novel hypothesis that efficient regulation of immune response requires immune cell intrinsic metabolism of D3. The proposed mechanism strikingly contrasts the current dogma, e.g., D3 is first activated in the liver by hydroxylation into 25(OH)D3 followed by a second hydroxylation at C1α by CYP27B1 in kidneys to produce 1,25(OH)2D3 that by interacting with vitamin D receptor (VDR) in innate and adaptive immune cells initiates a signaling cascade that is immunoregulatory. What has not been appreciated is the recent discovery of a non-canonical metabolic pathway of vitamin D activation that starts with hydroxylation of D3 by the steroidogenic enzyme CYP11A1 at C20 and produces 20(OH)D3 as the first metabolite that can down regulate T cell responses without the need for VDR. Importantly, CYP11A1 is expressed in T cells and other immune cells, providing an alternative mechanism for immune cell intrinsic production of non-canonical liver-independent active forms of D3 with critical role in immune regulation. Defects in this non-canonical pathway will have the phenotypic effects of vitamin D deficiency that cannot be rectified by canonical supplementation. Mechanistically, CYP11A1- dependent endogenously produced (20(OH)D3 and 20,23(OH)2D3 can exert immunoregulatory activity by (i) antagonizing NF-κB through classical pathway (VDR-dependent) and by (ii) suppressing Il17 expression through action as inverse agonists on RORα and RORγ. These pathways have not been considered as the mechanism for loss of vitamin D dependent regulation in SLE, which is the goal of this proposal. To address this challenge, the following aims are proposed: (1) To determine if canonical and/or non-canonical components of vitamin D signaling are decreased in immune cells from patients with SLE, and (2) To evaluate the hypothesis that the vitamin D3-dependent attenuation of NFκB and/or RORγ/α signaling pathways is defective in immune cells from SLE patients in comparison to normal subjects. The latter will include a highly mechanistic approach. The findings from this proposal will greatly advance the field with respect to vitamin D regulatory activity in T cells, B cells and monocytes within the context of SLE/autoimmunity. In addition, it is expected that they will pave the way for use of non-calcemic vitamin D derivatives for therapy of autoimmune disorders.

项目概要 系统性红斑狼疮 (SLE) 缺乏维生素 D3 (D3)，维生素 D3 是免疫系统的重要调节剂 系统，很常见，与疾病的严重程度和疲劳有关。然而，对维生素 D 的反应 即使在正常血清水平的情况下，补充也有一些益处和没有益处。 获得了 25(OH)D3（肝脏维生素 D3 代谢物）。这种可变响应的基本机制 是未知的，代表了我们知识中的一个关键差距。该提案将测试一个非常新颖的假设： 免疫反应的有效调节需要免疫细胞内在代谢 D3。拟议的 该机制与当前的教条形成鲜明对比，例如，D3 首先在肝脏中通过羟化作用被激活 25(OH)D3 随后在肾脏中被 CYP27B1 在 C1α 处进行第二次羟基化，产生 1,25(OH)2D3， 与先天性和适应性免疫细胞中的维生素 D 受体 (VDR) 相互作用，启动信号级联反应， 具有免疫调节作用。尚未得到重视的是最近发现的一种非典型代谢 维生素 D 激活途径始于类固醇生成酶 CYP11A1 对 D3 进行羟基化 C20 并产生 20(OH)D3 作为第一个代谢物，可以下调 T 细胞反应，而无需 对于VDR。重要的是，CYP11A1 在 T 细胞和其他免疫细胞中表达，提供了一种替代方案 免疫细胞内在产生非典型肝脏依赖性 D3 活性形式的机制 在免疫调节中发挥重要作用。这种非典型途径的缺陷将产生以下表型效应： 无法通过常规补充剂来纠正的维生素 D 缺乏症。从机制上讲，CYP11A1- 依赖内源性产生的（20(OH)D3 和 20,23(OH)2D3 可以通过 (i) 发挥免疫调节活性 通过经典途径（VDR 依赖性）拮抗 NF-κB 并通过 (ii) 抑制 Il17 表达 通过作为 RORα 和 RORγ 的反向激动剂发挥作用。这些途径尚未被视为 SLE 中维生素 D 依赖性调节丧失的机制，这是本提案的目标。致地址 针对这一挑战，提出了以下目标：（1）确定规范和/或非规范 SLE 患者的免疫细胞中维生素 D 信号传导成分减少，以及 (2) 评估 NFκB 和/或 RORγ/α 信号通路的维生素 D3 依赖性减弱的假设是 与正常人相比，系统性红斑狼疮患者的免疫细胞存在缺陷。后者将包括一个高度 机械方法。该提案的研究结果将极大地推进维生素 D 领域的发展 SLE/自身免疫背景下 T 细胞、B 细胞和单核细胞的调节活性。此外，它是 预计它们将为使用非钙血症维生素 D 衍生物治疗自身免疫性疾病铺平道路 失调。

项目成果

Evidence for Involvement of Nonclassical Pathways in the Protection From UV-Induced DNA Damage by Vitamin D-Related Compounds.

• DOI: 10.1002/jbm4.10555
• 发表时间: 2021-12
• 期刊: JBMR plus
• 影响因子: 3.8
• 作者: De Silva WGM;Han JZR;Yang C;Tongkao-On W;McCarthy BY;Ince FA;Holland AJA;Tuckey RC;Slominski AT;Abboud M;Dixon KM;Rybchyn MS;Mason RS
• 通讯作者: Mason RS

Melanoma, Melanin, and Melanogenesis: The Yin and Yang Relationship.

• DOI: 10.3389/fonc.2022.842496
• 发表时间: 2022
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Slominski RM;Sarna T;Płonka PM;Raman C;Brożyna AA;Slominski AT
• 通讯作者: Slominski AT

Recent Advances in Vitamin D Biology: Something New under the Sun.

维生素 D 生物学的最新进展：阳光下的新事物。

• DOI: 10.1016/j.jid.2023.07.003
• 发表时间: 2023
• 期刊: The Journal of investigative dermatology
• 作者: Slominski,AndrzejT;Tuckey,RobertC;Jetten,AntonM;Holick,MichaelF
• 通讯作者: Holick,MichaelF

Selective ability of rat 7-Dehydrocholesterol reductase (DHCR7) to act on some 7-Dehydrocholesterol metabolites but not on lumisterol metabolites.

• DOI: 10.1016/j.jsbmb.2021.105929
• 发表时间: 2021-09
• 期刊: The Journal of steroid biochemistry and molecular biology
• 作者: Tuckey RC;Tang EKY;Chen YA;Slominski AT
• 通讯作者: Slominski AT

Protective Role of Melatonin and Its Metabolites in Skin Aging.

• DOI: 10.3390/ijms23031238
• 发表时间: 2022-01-22
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Bocheva G;Slominski RM;Janjetovic Z;Kim TK;Böhm M;Steinbrink K;Reiter RJ;Kleszczyński K;Slominski AT
• 通讯作者: Slominski AT