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.

摘要 骨骼的老化更容易发展成自身免疫性疾病，如类风湿性关节炎（RA）。 破骨细胞活性的增加和骨吸收的增加是骨骼衰老的部分原因。 我们已经表明，在软骨下骨破骨细胞形成的异常激活启动解偶联 在RA和骨关节炎（OA）中，关节重塑活性诱导关节变性。破骨细胞升高 软骨下骨的活动也是关节疼痛的原因。然而， 破骨细胞融合和骨吸收的增加在RA中尚不清楚。有趣的是，血清中的唾液酸水平和 细胞受体唾液酸化在骨骼衰老和自身免疫过程中持续增加 疾病我们发现TLR 2的唾液酸化诱导与Siglec 15结合，从而启动破骨细胞融合以治疗骨丢失。 Trap+单核细胞与RANKL发生细胞-细胞融合，形成Trap+多核破骨细胞。的 RANKL诱导破骨细胞融合和成熟的机制尚未完全了解。我们的初步结果 RANKL诱导前破骨细胞中α 2，3-唾液酸转移酶ST 3Gal 1的转录。值得注意的是， TLR 2被ST 3Gal 1唾液酸化诱导与Siglec 15结合，Siglec 15是TLR 2的唾液酸结合凝集素的成员。 免疫球蛋白超家族，以促进破骨细胞融合骨吸收。 平行地，我们的初步结果还显示唾液酸化的TLR 2与Siglec 15的结合诱导了偏向性的细胞凋亡。 RA发病时CD 4 + T细胞的Th 17分化我们现在知道Th 17 T细胞参与了 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） 和系统性红斑狼疮（SLE）。理解Th 17细胞在免疫系统中的不同功能是至关重要的。 稳态和疾病状态。Th 17细胞还促进B细胞成熟产生自身免疫抗体 一代最重要的是，我们的初步研究结果表明，大豆皂苷Bb，一种三萜皂苷， 大豆能有效地抑制老年和RA小鼠的α 2，3-唾液酸转移酶活性。因此，我们假设， 唾液酸化TLR 2诱导的破骨细胞融合和CD 4 + T细胞偏向Th 17分化 加速骨骼退化，易患自身免疫性疾病，如RA。在 在这项研究中，我们将首先描述唾液酸化TLR 2诱导破骨细胞融合的机制， 目标1。然后，我们将研究类风湿关节炎发病时TLR 2唾液酸化对T细胞的影响。我们将最终检查 三七皂苷Bb唾液酸转移酶抑制剂对类风湿关节炎的治疗作用。TLR 2唾液酸化的抑制 大豆皂甙Bb可减轻年龄诱导的Th 17分化和破骨细胞融合的偏向。