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: 10430544
• 负责人: Xu Cao
• 金额: $ 48.98万
• 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/10430544
• 关键词: 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; Interferons; Interleukin-10; JAK2 gene; Ligands; Macrophage Colony-Stimulating Factor; Marrow; Mass Spectrum Analysis; Measures; Modeling; Mononuclear; Multiple Sclerosis; Mus; Neuraminidase; Osteoclasts; Pathogenesis; Pathway interactions; Persons; Population; Process; 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; Testing; Therapeutic; Therapeutic Effect; Transgenic Organisms; aged; bone; bone loss; bone mass; cytokine; glycosylation; inhibitor; joint destruction; macrophage; 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 骨骼老化变得更容易发生自身免疫性疾病，如类风湿性关节炎(RA)。 破骨细胞活性增强和骨吸收是衰老过程中骨骼退化的部分原因。 我们已经证明，软骨下骨中破骨细胞形成的异常激活是解偶联的。 在RA和骨关节炎(OA)中，重塑活动都会导致关节退行性变。升高的破骨细胞 软骨下骨的活动也是关节疼痛的原因。然而，信号转导机制 类风湿关节炎患者破骨细胞融合和骨吸收增加的情况尚不清楚。有趣的是，血清和血液中的唾液酸水平 细胞受体唾液酸化持续增加可能与骨骼老化和自身免疫有关 疾病。我们发现TLR2的唾液酸化诱导了与Siglec15的结合，从而启动了破骨细胞的融合，从而导致骨丢失。 TRAP+单核细胞与RANKL进行细胞-细胞融合，形成Trap+多核破骨细胞。这个 RANKL诱导破骨细胞融合成熟的机制尚不完全清楚。我们的初步结果 结果显示，RANKL可诱导破骨前细胞α2，3-唾液酸转移酶ST3Gal1的转录。值得注意的是， ST3Gal1唾液酸化TLR2诱导其与唾液酸结合凝集素Siglec15的结合 免疫球蛋白超家族，促进破骨细胞融合促进骨吸收。 同时，我们的初步结果还表明，唾液酸化的TLR2与Siglec 15的结合导致了偏向 类风湿性关节炎发病初期的Th17细胞分化。我们现在知道Th17T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) 系统性红斑狼疮(SLE)。了解Th17细胞的分化功能是非常重要的。 动态平衡和疾病状态。Th17细胞也促进自身免疫抗体的B细胞成熟 一代。最重要的是，我们的初步结果表明，大豆皂苷BB是大豆中的一种三萜皂苷 大豆有效抑制老龄和RA小鼠α2，3-唾液酸基转移酶活性。因此，我们假设 唾液酸化TLR2诱导的破骨细胞融合和老化过程中CD4+T细胞的偏向Th17分化 加速骨骼退化，易患自身免疫性疾病，如类风湿性关节炎。在……里面 在这项拟议的研究中，我们将首先表征唾液酸化TLR2诱导的破骨细胞融合的机制 目的1.研究唾液酸化TLR2对RA发病时T细胞的影响。我们将最终检查 大豆皂苷BB唾液酸转移酶抑制剂对类风湿关节炎的治疗作用对TLR2唾液酸化的抑制作用 大豆皂苷BB可减轻年龄诱导的Th17偏向分化和破骨细胞融合。