Identifying a novel pathway that regulates RA immunometabolism

鉴定调节 RA 免疫代谢的新途径

• 批准号: 10535288
• 负责人: SHIVA SHAHRARA
• 金额: $ 70.84万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535288
• 关键词: Adoptive Transfer; Affect; Arthritis; Attenuated; Autoimmune Diseases; Binding; Biochemical Pathway; Blood; Blood Circulation; CD14 gene; CD86 gene; Cells; Collagen Arthritis; Colony-Stimulating Factor Receptors; Degenerative polyarthritis; Disease; Disease Progression; Effectiveness; Exhibits; Experimental Arthritis; FRAP1 gene; Functional disorder; Glycolysis; Goals; HIF1A gene; Impairment; Infiltration; Inflammatory; Intercept; Interleukin-1 beta; Interleukin-6; Joints; Ligands; Ligation; Link; Mediating; Metabolic; Metabolic Pathway; Mitochondria; Molecular; Monokines; Mus; Myelogenous; Myeloid Cells; Osteoclasts; Oxidative Phosphorylation; Pain; Pathogenicity; Pathway interactions; Patients; Persons; Phenotype; Phosphorylation; Play; Pre-Clinical Model; Radiology Specialty; Rheumatoid Arthritis; Role; SLC2A1 gene; Signal Transduction; Study models; Swelling; Synovial Fluid; TNF gene; Testing; Therapeutic; Time; Tissues; Tyrosine; Up-Regulation; arthritis therapy; arthropathies; base; bone erosion; cytokine; glucose metabolism; glucose uptake; imprint; innovation; interest; joint inflammation; macrophage; monocyte; neutralizing antibody; novel; novel therapeutic intervention; patient response; pre-clinical; protein expression; receptor; response; small hairpin RNA; syndecan

Rheumatoid arthritis (RA) is the most common autoimmune disease, which affects 2.5 million people in the US. It has been shown that joint monocyte infiltration and differentiation into inflammatory macrophages (MΦs) play a key role in disease progression. Patients with a positive response to RA therapy, exhibit a reduced number of MΦs, joint inflammation, pain & radiological damage. In contrast, in non-responsive patients, the number of inflammatory MΦs is expanded along with skewed metabolic rewiring towards glycolysis and away from mitochondrial oxidative phosphorylation. Hence, to find a novel therapeutic strategy, there is a critical unmet need to elucidate the molecular mechanism by which naïve joint cells are reprogrammed into glycolytic RA MΦs. We show for the first time, that a specific cytokine rewires the naïve M0 cells into glycolytic MΦs that produce high levels of inflammatory monokines and metabolites. Notably, these glycolytic MΦs are primed to differentiate into mature osteoclasts. Notably, dysregulation of syndecan (SDC)1 impairs secretion of the inflammatory monokines, polarization of the glycolytic CD14+CD86+GLUT1+ MΦs, and remodeling of the primed glycolytic cells into mature osteoclasts facilitated by the cytokine of interest. Based on these novel observations, we hypothesize that binding of the cytokine of interest to SDC1 reprograms the naïve cells into glycolytic MΦs and mature osteoclasts, and blockade of SDC1 or the activated metabolic intermediates will attenuate arthritis. To test our hypothesis, we will determine if inhibition of the SDC1 or the identified glycolytic intermediates will impede the remodeling of naïve cells into metabolically active RA MΦs and mature osteoclasts using the early and late-stage patients. Next, we will delineate if the adoptive transfer of fully differentiated glycolytic MΦs can restore preclinical arthritis in the absence of metabolic factors linked to SDC1. Last, we will investigate whether deregulation of SDC1 or the master regulator of glucose metabolism will attenuate experimental arthritis. By integrating mechanistic RA cellular studies and preclinical models, we aim to delineate pathways by which the metabolically active MΦs advance joint disease. Our proposed approach will answer several fundamental questions including; 1) What are the metabolic machinery activated in RA MΦs and experimental arthritis, 2) Whether RA MΦ-regulated inflammatory and erosive phenotypes will be reversed by dysregulation of glycolytic intermediates and 3) Does targeting the hypermetabolic activity in MΦs represents a new therapeutic approach for RA.

类风湿性关节炎(RA)是最常见的自身免疫性疾病，全世界有250万人患病 我们。已有研究表明，联合单核细胞的侵袭和分化为炎性巨噬细胞(MΦS) 在疾病发展过程中起着关键作用。对RA治疗呈阳性反应的患者数量减少 MΦS，关节炎症、疼痛和放射损伤。相比之下，在无反应的患者中， 炎症性MΦS随着偏斜的代谢重排向糖酵解而不是 线粒体氧化磷酸化。因此，要找到一种新的治疗策略，有一个关键的未满足 需要阐明幼稚关节细胞被重新编程为糖酵解RA MΦS的分子机制。 我们首次证明，一种特定的细胞因子将幼稚的M0细胞重新连接到糖酵解MΦS 产生高水平的炎症性单因子和代谢物。值得注意的是，这些糖酵解MΦS已经准备好 分化为成熟的破骨细胞。值得注意的是，Syndecan(SDC)1的调节失调损害了 炎性单因子、糖酵解CD14+CD86+Glut1+MΦS的极化与血管重构 在感兴趣的细胞因子的促进下，将糖酵解细胞诱导成成熟的破骨细胞。 基于这些新的观察结果，我们假设感兴趣的细胞因子与SDC1的结合 将幼稚细胞重新编程为糖酵解MΦS和成熟破骨细胞，并阻断SDc1或活化的 代谢中间体将减轻关节炎。为了验证我们的假设，我们将确定SDC1的抑制是否 或者，已确定的糖酵解中间体将阻碍幼稚细胞重塑为代谢活性的RA MΦS与成熟破骨细胞共用的早期和晚期患者。接下来，我们将描绘领养人是否 转移全分化糖酵解MΦS可在无代谢因素的情况下修复临床前关节炎 链接到SDC1。最后，我们将调查是否放松对SDC1的管制或葡萄糖的主调节器 新陈代谢会减轻实验性关节炎。通过将机械性RA细胞研究和临床前研究相结合 通过建立模型，我们的目标是描绘代谢活跃的MΦS促进关节疾病发展的途径。我们的 提出的方法将回答几个基本问题，包括：1)代谢机制是什么 激活的RA MΦS和实验性关节炎2)RA MΦ是否调节炎症和侵蚀性 糖酵解中间产物的失调将逆转表型，3)靶向 MΦS的高代谢活性为RA的治疗提供了新的途径。