Identifying a novel pathway that regulates RA immunometabolism

鉴定调节 RA 免疫代谢的新途径

基本信息

批准号：
10662549
负责人：
SHIVA SHAHRARA
金额：
$ 71.48万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2022-07-08 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662549
关键词：
Adoptive Transfer Affect Arthritis Attenuated Autoimmune Diseases Binding Biochemical Pathway Blood CD14 gene CD86 gene Cells Circulation 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 Macrophage 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 bone erosion cytokine glucose metabolism glucose uptake imprint innovation interest joint inflammation monocyte neutralizing antibody novel novel therapeutic intervention patient response pre-clinical programs protein expression receptor response small hairpin RNA syndecan

项目摘要

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，影响着全球 250 万人。美国已经表明，关节单核细胞浸润并分化为炎症巨噬细胞（MΦs）对 RA 治疗有积极反应的患者数量减少。相反，在无反应的患者中，MΦ 的数量、关节炎症、疼痛和放射损伤的数量。炎症 MΦ 随着偏向糖酵解和远离糖酵解的代谢重新布线而扩大因此，要找到一种治疗新策略，还有一个关键的未满足的问题。需要阐明幼稚关节细胞被重编程为糖酵解 RA MΦ 的分子机制。我们首次证明，特定的细胞因子将初始 M0 细胞重新连接成糖酵解 MΦ，产生高水平的炎症单核因子和代谢物值得注意的是，这些糖酵解 MΦ 已做好准备。分化为成熟的破骨细胞值得注意的是，多聚糖 (SDC)1 的失调会损害破骨细胞的分泌。炎症单核因子、糖酵解 CD14+CD86+GLUT1+ MΦs 的极化以及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，我们勇敢地发现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 MΦ 和成熟破骨细胞，并阻断 SDC1 或激活的为了检验我们的假设，我们将确定是否抑制 SDC1。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跃的 RA 使用早期和晚期患者的 MΦs 和成熟破骨细胞接下来，我们将描述是否采用收养。完全分化的糖酵解 MΦ 的转移可以在缺乏代谢因素的情况下恢复临床前关节炎最后，我们将研究 SDC1 或葡萄糖的主调节因子是否失调。通过整合机制性 RA 细胞研究和临床前研究，新陈代谢将减轻实验性关节炎。模型中，我们的目标是描绘代谢活跃的 MΦ 促进关节疾病的途径。所提出的方法将回答几个基本问题，包括：1）什么是代谢机制？在 RA MΦ 和实验性关节炎中激活，2) RA MΦ 是否调节炎症和糜烂表型将因糖酵解中间体的失调而逆转，并且 3) 是否针对 MΦs 的代谢亢进代表了 RA 的一种新治疗方法。