# Identifying a novel pathway that regulates RA immunometabolism

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $714,758

## Abstract

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.

## Key facts

- **NIH application ID:** 10662549
- **Project number:** 5R01AI167155-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** SHIVA SHAHRARA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $714,758
- **Award type:** 5
- **Project period:** 2022-07-08 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10662549

## Citation

> US National Institutes of Health, RePORTER application 10662549, Identifying a novel pathway that regulates RA immunometabolism (5R01AI167155-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10662549. Licensed CC0.

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