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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的骨骼老化变得更容易患上类风湿性关节炎（RA）等自身免疫性疾病。破骨细胞活性和骨吸收的增加是衰老过程中骨骼退化的部分原因。我们已经表明，软骨下骨中破骨细胞形成的异常激活引发了非耦合的破骨细胞的重塑活动会导致 RA 和骨关节炎 (OA) 中的关节退化。软骨下骨的活动也是造成关节疼痛的原因，但是其信号机制。 RA 中破骨细胞融合和骨吸收的增加尚不清楚。细胞受体的唾液酸化在骨骼老化和自身免疫过程中不断增加我们发现 TLR2 的唾液酸化诱导与 Siglec15 的结合，启动破骨细胞融合，从而导致骨质流失。 Trap+ 单核细胞与 RANKL 进行细胞-细胞融合，形成 Trap+ 多核破骨细胞。我们的初步结果尚未完全了解 RANKL 诱导破骨细胞融合和成熟的机制。表明 RANKL 诱导前破骨细胞中 α2,3-唾液酸转移酶 ST3Gal1 的转录。 ST3Gal1 对 TLR2 的唾液酸化诱导与 Siglec15 的结合，Siglec15 是唾液酸结合凝集素的成员免疫球蛋白超家族，促进破骨细胞融合，促进骨吸收。与此同时，我们的初步结果还表明，唾液酸化 TLR2 与 Siglec 15 的结合诱导了偏向性。 RA 发生时 CD4+ T 细胞的 Th17 分化我们现在知道 Th17 T 细胞参与了 RA 发展。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) 中，了解 Th17 细胞的不同功能至关重要。稳态和疾病状态下 Th17 细胞也会促进自身免疫抗体的 B 细胞的成熟。最重要的是，我们的初步结果表明，大豆皂苷 Bb 是一种三萜皂苷。大豆，有效抑制老年小鼠和 RA 小鼠的 α2,3-唾液酸转移酶活性。衰老过程中唾液酸化 TLR2 诱导的破骨细胞融合和 CD4+ T 细胞的 Th17 分化加速骨骼退化，容易患上 RA 等自身免疫性疾病。在所提出的研究中，我们将首先描述唾液酸化 TLR2 诱导的破骨细胞融合的机制目标 1. 然后我们将研究 RA 发作时 TLR2 唾液酸化对 T 细胞的影响。大豆皂苷 Bb 唾液酸转移酶抑制剂抑制 TLR2 唾液酸化对 RA 的治疗作用。大豆皂苷 Bb 可以减轻年龄引起的 Th17 和破骨细胞融合的偏向分化。