Immunometabolism in rheumatoid arthritis

Immunometabolism in rheumatoid arthritis (RA) is the study of how metabolic reprogramming within immune and stromal cells actively shapes synovial inflammation, immune cell phenotype, and joint destruction. Cellular metabolism operates not as a passive energetic backdrop but as a regulatory driver of chronic autoimmunity in the rheumatoid joint.

The metabolic landscape of the rheumatoid synovium

RA is a chronic autoimmune disease defined by persistent synovial inflammation, immune cell infiltration, autoantibody production, pannus formation, and progressive cartilage and bone destruction. Although traditionally framed around cytokines, autoreactive lymphocytes, macrophages, and fibroblast-like synoviocytes (FLS), the field now recognizes that metabolic reprogramming actively shapes immune cell function, survival, and inflammatory output.¹,²

At sites of inflammation, immune cells enter a metabolically demanding microenvironment. The inflamed synovium is hypoxic, nutrient-restricted, acidic, and enriched in inflammatory cytokines and metabolites such as lactate. These conditions share features with the tumor microenvironment, including high glucose consumption, local glucose deprivation, elevated glycolytic activity, and accumulation of immunomodulatory by-products.³ Within this niche, immune and stromal cells adapt their metabolism to sustain activation, proliferation, cytokine production, and tissue-invasive behavior.

Glycolysis supports inflammatory activation

One of the most prominent immunometabolic features of RA is a shift toward aerobic glycolysis. In rheumatoid synovial tissue and peripheral immune cells, increased glucose uptake and elevated lactate production reflect enhanced glycolytic flux. Upregulation of glucose transporters such as GLUT1, together with glycolytic enzymes including HK1, GAPDH, PKM, and LDH, supports rapid ATP generation and provides biosynthetic intermediates required for inflammatory responses.⁴

This program is reinforced by hypoxia-driven signaling through HIF-1α, which promotes glycolytic gene expression and helps immune cells adapt to the oxygen-poor synovial microenvironment. The intersection between hypoxia sensing and metabolic rewiring establishes a self-reinforcing loop in which inflammation, oxygen limitation, and glycolysis mutually amplify one another.

Macrophages: Glycolysis and inflammatory polarization

In macrophages, glycolytic reprogramming is closely linked to inflammatory polarization. RA macrophages can display features of an M1-like phenotype, including increased glycolysis, activation of mTOR-related pathways, and production of cytokines such as IL-1β, TNF-α, and IL-6.² Inhibiting glycolysis has been reported to reduce pro-inflammatory macrophage activity and promote a shift toward resolving, M2-like phenotypes.

T cells: Subset-specific metabolic adaptations

T cells in RA undergo disease-associated metabolic changes that differ between subsets. CD8+ T cells show increased aerobic glycolysis and elevated LDHA activity, supporting inflammatory crosstalk with other immune cells. CD4+ T cells display altered glycolytic regulation and increased use of the pentose phosphate pathway, a route supported by G6PD that provides NADPH and ribose intermediates for redox balance and nucleotide synthesis.⁵ These adaptations influence the balance between inflammatory Th17 cells and regulatory T cells (Tregs).

B cells: Metabolism supporting autoimmunity

B cells are also metabolically rewired in RA. Increased glycolytic activity in peripheral B cells has been linked to inflammatory signaling and may support autoantibody production, antigen presentation, and T cell activation.³ Through interactions with T cells, including costimulatory pathways, metabolically active B cells help sustain pathogenic T helper responses.

Lactate acts as more than a waste product

Lactate accumulation is a hallmark of the inflamed RA synovium. Although often viewed as an endpoint of glycolysis, lactate also functions as a signaling metabolite that links metabolism, inflammation, and immune regulation. Hypoxia, high glycolytic flux, and impaired metabolic clearance all contribute to its accumulation. Lactate transporters including SLC16A1 and SLC16A3 are expressed by synovial fibroblasts and macrophages, enabling lactate exchange within the inflammatory niche.⁶

In RA, lactate exerts cell-specific effects. It promotes glycolytic and invasive behavior in synovial fibroblasts while altering macrophage metabolism and inflammatory function. In CD4+ T cells, lactate uptake through transporters such as SLC5A12 has been associated with increased IL-17 production, enhanced fatty acid synthesis, and reduced glycolysis, thereby supporting Th17-driven inflammation.⁶ These findings highlight lactate as a metabolic checkpoint that can reshape immune cell differentiation and perpetuate chronic synovitis.

Mitochondrial metabolism and oxidative stress

Although glycolysis is strongly emphasized in RA immunometabolism, mitochondrial pathways are equally important. Mitochondria regulate ATP production, reactive oxygen species (ROS) generation, apoptosis, and metabolite signaling through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Altered activity of TCA cycle enzymes and mitochondrial membrane proteins influences immune cell survival, inflammatory signaling, and redox balance in RA.⁵

Mitochondrial stress amplifies inflammation through ROS and danger-associated signals. In immune cells and synovial fibroblasts, mitochondrial dysfunction promotes NF-κB activation, inflammasome signaling, and altered apoptosis. RA is therefore not simply a glycolytic disease but a condition in which glycolysis, OXPHOS, mitochondrial remodeling, and redox regulation are dynamically interconnected.

Amino acid and lipid metabolism sustain immune activation

Activated immune cells require amino acids to support proliferation, cytokine production, redox control, and biosynthesis. Glutamine metabolism is particularly important because glutamine feeds the TCA cycle and supports nucleotide, amino acid, and antioxidant metabolism. Transporters and enzymes such as ASCT2, CD98, and GLS mark glutamine uptake and catabolism in inflammatory immune cells.⁴ Arginine metabolism and one-carbon pathways, including serine–glycine flux through SHMT2, further connect amino acid handling to nucleotide synthesis and methylation reactions relevant to lymphocyte expansion.

Lipid metabolism is equally influential. Fatty acid uptake via CD36, de novo lipogenesis through ACLY and FASN, and fatty acid oxidation (FAO) mediated by CPT1A collectively shape immune cell phenotype.² Th17 differentiation is favored by fatty acid synthesis, whereas Treg stability and macrophage resolution depend on FAO. Lipid remodeling therefore helps determine whether the synovial immune compartment leans toward inflammation or resolution.

Redox balance and NAD+ signaling

Inflamed RA tissue is marked by oxidative stress, which damages proteins, lipids, and DNA while modulating inflammatory signaling. Immune cells must balance ROS production with antioxidant defenses. Metabolic pathways that generate NADPH, particularly the pentose phosphate pathway through G6PD, help maintain redox balance and support biosynthesis. Antioxidant systems such as glutathione and peroxiredoxins protect metabolically stressed immune cells.⁵

Sirtuin signaling provides another link between metabolism, inflammation, and cellular stress. SIRT1, an NAD+-dependent deacetylase, regulates inflammatory signaling, mitochondrial function, and metabolic adaptation. Because NAD+ availability reflects cellular metabolic state, SIRT1-related pathways connect nutrient sensing to immune regulation in chronic inflammatory diseases such as RA.

Metabolic pathways and immune function in RA at a glance

Why does immunometabolism matter for RA research?

Immunometabolism reframes RA as a disease in which immune cells are actively reprogrammed by the synovial microenvironment and, in turn, reshape it through metabolite release, cytokine production, and cell–cell communication. Glycolysis, lactate signaling, mitochondrial function, amino acid handling, lipid remodeling, and redox pathways all contribute to the persistence of synovial inflammation.¹ This integrated view opens opportunities for biomarker discovery and therapeutic strategies that modulate immune cell function rather than broadly suppress immunity.

How does the synovial microenvironment reprogram immune cells?

The rheumatoid synovium imposes hypoxia, nutrient limitation, acidosis, and cytokine excess on infiltrating immune cells. These stresses activate HIF-1α and mTOR signaling, upregulate glucose and amino acid transporters, and drive glycolytic and biosynthetic programs. The resulting metabolic state stabilizes pro-inflammatory phenotypes in macrophages, Th17 cells, and B cells while impairing Treg function, reinforcing chronic inflammation.

Can metabolic targeting complement current RA therapies?

Metabolic targeting offers a route to modulate — rather than broadly suppress — immune function. Interfering with glycolysis, glutaminolysis, lactate transport, or FAO can selectively destabilize inflammatory phenotypes while preserving regulatory populations. Combined with cytokine-directed biologics, metabolic strategies may improve response durability, address treatment resistance, and enable more precise disease control in RA.

FAQs

References

1. Liu X, Wang J, Lou T, et al. Immunometabolism in rheumatoid arthritis: mechanisms, biomarkers, and the path to precision medicine. Frontiers in Immunology. 2026.
2. Xie R, Chen Z, Deng S, Jiang X, Feng Y, Zhao W. Roles of immune cell metabolism in rheumatoid arthritis. Frontiers in Immunology. 2026.
3. Jang S, Kwon E-J, Lee JJ. Rheumatoid arthritis: pathogenic roles of diverse immune cells. International Journal of Molecular Sciences. 2022.
4. Cellular metabolic adaptations in rheumatoid arthritis and their therapeutic implications. Nature Reviews Rheumatology. 2022.
5. Metabolic regulation of the immune system in health and diseases. Signal Transduction and Targeted Therapy. 2024.
6. Pucino V, Certo M, Bulusu V, et al. Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T cell metabolic rewiring. Cell Metabolism. 2019.