Identifying a novel pathway that regulates RA immunometabolism

风湿性关节炎（RA）是最常见的自身免疫性疾病，影响250万人， 我们研究表明，关节单核细胞浸润并分化为炎性巨噬细胞（MΦs） 在疾病进展中起关键作用。对RA治疗有阳性反应的患者， MΦs、关节炎、疼痛和放射性损伤。相反，在无反应患者中， 炎症性MΦ沿着扩张，伴随着偏向糖酵解的代谢重连， 线粒体氧化磷酸化。因此，要找到一种新的治疗策略， 需要阐明幼稚关节细胞重编程为糖酵解性RA MΦ的分子机制。 我们首次发现，一种特定的细胞因子将幼稚的M0细胞重新连接成糖酵解的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被启动， 分化成成熟的破骨细胞。值得注意的是，多配体蛋白聚糖（SDC）1的调节异常损害多配体蛋白聚糖的分泌。 炎性单核因子，糖酵解CD14+CD86+GLUT1+ MΦ的极化，以及 通过感兴趣的细胞因子促进糖酵解细胞转化为成熟的破骨细胞。 基于这些新的观察，我们假设感兴趣的细胞因子与SDC1的结合 将幼稚细胞重编程为糖酵解MΦ和成熟破骨细胞，并阻断SDC1或活化的 代谢中间物将减弱关节炎。为了验证我们的假设，我们将确定是否抑制SDC1 或者糖酵解中间体会阻碍幼稚细胞向代谢活性RA的重塑 MΦ和成熟破骨细胞使用早期和晚期患者。接下来，我们将描述收养人是否 完全分化的糖酵解MΦ的转移可以在没有代谢因素的情况下恢复临床前关节炎 连接到SDC1。最后，我们将研究是否SDC1或葡萄糖的主要调节器的失调， 新陈代谢会减弱实验性关节炎通过整合RA细胞机制研究和临床前研究， 模型，我们的目的是描绘代谢活跃的MΦ推进关节疾病的途径。我们 提出的方法将回答几个基本问题，包括：1）什么是代谢机制 RA MΦ和实验性关节炎中活化，2）RA MΦ是否调节炎症和侵蚀 表型将通过糖酵解中间体的失调而逆转，以及3）靶向糖酵解中间体的剂量 MΦs的高代谢活性代表了RA的新治疗方法。

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.