Identifying a novel pathway that regulates RA immunometabolism

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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.