Sialylation of TLR2 Induces Osteoclast Fusion and Th 17 differentiation During Aging

TLR2 唾液酸化诱导衰老过程中破骨细胞融合和 Th 17 分化

• 批准号: 10650877
• 负责人: Xu Cao
• 金额: $ 48.66万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650877
• 关键词: Acceleration; Adult; Age; Aging; Arthralgia; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Binding; Bone Diseases; Bone Resorption; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell fusion; Cells; Collagen Arthritis; Degenerative polyarthritis; Deterioration; Development; Disease; Equilibrium; Excision; Family; Gene Expression Profile; Generations; Genetic Transcription; Immunoglobulins; Inflammatory; Inflammatory Bowel Diseases; Interferon Type II; Interleukin-10; JAK2 gene; Ligands; Macrophage; Macrophage Colony-Stimulating Factor; Marrow; Mass Spectrum Analysis; Measures; Modeling; Mononuclear; Multiple Sclerosis; Mus; Neuraminidase; Nuclear; Osteoclasts; Pathogenesis; Pathway interactions; Persons; Population; Predisposition; Process; Proliferating; Proteins; RANK protein; Regulatory T-Lymphocyte; Rheumatoid Arthritis; Saponins; Serum; Sialic Acids; Sialyltransferases; Signal Transduction; Site; Skeleton; Soyasaponin; Systemic Lupus Erythematosus; T-Lymphocyte; TNF gene; Terpenes; Testing; Therapeutic; Therapeutic Effect; Transgenic Organisms; aged; bone; bone loss; bone mass; cytokine; glycosylation; inhibitor; joint destruction; member; monocyte; osteoclastogenesis; receptor; sialic acid binding Ig-like lectin; sialic acid-binding lectin; sialylation; soy; subchondral bone; therapeutic evaluation

Abstract Aging of skeleton becomes more susceptible to develop autoimmune disease such as rheumatoid arthritis (RA). Increased osteoclast activity and bone resorption is partly responsible for deterioration of skeleton during aging. We have shown that aberrant activation of osteoclast formation in the subchondral bone initiates uncoupled remodeling activity to induce degeneration of joints in both RA and osteoarthritis (OA). The elevated osteoclast activity in the subchondral bone is also responsible for the joint pain. However, the signaling mechanism of increased osteoclast fusion and bone resorption is unclear in RA. Interestingly, sialic acid level in serum and sialylation of cellular receptors continuously increase during with implication of skeleton aging and autoimmune disease. We found that sialylation of TLR2 induced binding to Siglec15 to initiate osteoclast fusion for bone loss. Trap+ mononuclear cells with RANKL undergo cell-cell fusion to form Trap+ multinuclear osteoclasts. The mechanism of RANKL-induced osteoclast fusion and maturation are not fully understood. Our preliminary results showed that RANKL induced transcription of α2,3-sialyltransferase ST3Gal1 in preosteoclasts. Noteworthy, the sialylation of TLR2 by ST3Gal1 induces binding to Siglec15, a member of sialic acid-binding lectins of the immunoglobulin superfamily, to promote osteoclast fusion for bone resorption. In parallel, our preliminary results also showed that the binding of sialylated TLR2 to Siglec 15 induced biased Th17 differentiation of CD4+ T cells at onset of RA development. We now know that Th17 T cells are involved in nearly all major autoimmune diseases, including RA, multiple sclerosis (MS), inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). It is critical to understand the divergent functions of Th17 cells in homeostatic and disease states. Th17 cells also promote the maturation of B cells for autoimmune antibody generation. Most importantly, our preliminary results showed that soyasaponin Bb, a triterpenoid saponin from soy, effectively inhibited α2,3-sialyltransferases activity in both aged and RA mice. Thus, we hypothesize that sialylation TLR2-induced osteoclast fusion and biased Th17 differentiation of CD4+ T cells during aging accelerates skeleton deterioration susceptible to development of autoimmune disease such as RA. In the proposed study, we will first characterize mechanism of sialylated TLR2-induced osteoclast fusion in Specific Aim 1. We will then investigate the effect of sialylation of TLR2 on T cells at onset of RA. We will finally examine the therapeutic effect of Soyasaponin Bb sialyltransferase inhibitor on RA. Inhibition of TLR2 sialylation by soyasaponin Bb could mitigate age-induced biased differentiation of Th17 and osteoclast fusion.

抽象的 骨骼的衰老变得更容易发生自身免疫性疾病，例如类风湿关节炎（RA）。 破骨细胞活性和骨骼分辨率的增加是确定衰老过程中骨骼恶化的部分原因。 我们已经表明，在软骨下骨中的破骨细胞形成异常激活启动未偶联 重塑活性以诱导RA和骨关节炎（OA）的关节变性。升高的破骨细胞 软骨下骨的活性也导致关节疼痛。但是， 在RA中尚不清楚破骨细胞融合和骨骼分辨率的增加。有趣的是，血清中的唾液酸水平和 在与骨骼老化和自身免疫的影响期间，细胞接收器的溶解度不断增加 疾病。我们发现，TLR2的溶解度诱导与SigleC15的结合，以引发破骨细胞融合以进行骨丢失。 带有RANKL的TRAP+单核细胞会经历细胞细胞融合，形成陷阱+多核破骨细胞。这 RANKL诱导的破骨细胞融合和成熟的机制尚不完全了解。我们的初步结果 结果表明，RANKL诱导的α2,3-溶解酶ST3GAL1在pe骨前细胞中的转录。值得注意的 ST3GAL1对TLR2的溶解性诱导与SigleC15的结合，SigleC15是唾液酸结合讲座的成员 免疫球蛋白超家族，以促进破骨细胞融合进行骨骼分辨率。 同时，我们的初步结果还表明，溶解的TLR2与SIGLEC 15诱导的偏置的结合 在RA发育开始时，CD4+ T细胞的Th17分化。我们现在知道Th17 T细胞参与 几乎所有主要的自身免疫性疾病，包括RA，多发性硬化症（MS），炎症性肠病（IBD） 和全身性红斑狼疮（SLE）。了解Th17细胞在 稳态和疾病状态。 Th17细胞还促进了自身免疫性抗体的B细胞的成熟 一代。最重要的是，我们的初步结果表明，大豆蛋白BB，一种三萜皂苷 大豆有效地抑制了老年和RA小鼠的α2,3-溶解酶活性。那我们假设 lylylation TLR2诱导的破骨细胞融合和CD4+ T细胞的Th17分化在衰老期间 加速骨骼定义易受自身免疫性疾病（例如RA）的发展。在 拟议的研究，我们将首先表征溶解的TLR2诱导的破骨细胞融合的机理 AIM 1。然后，我们将在RA发作时研究TLR2溶解对T细胞的影响。我们终于会检查 大豆蛋白BB siAllyltransferass抑制剂对RA的治疗作用。通过抑制TLR2溶解 大豆蛋白BB可以减轻年龄引起的Th17和破骨细胞融合的偏差分化。