Effects of Metabolic Dysregulation on Macrophage Polarization in Rheumatoid Arthritis

Arthritis Rheumatol. 2026 Jun 18. doi: 10.1002/art.70253. Online ahead of print.

ABSTRACT

Rheumatoid arthritis (RA) is a systemic autoimmune disease driven by complex immune dysregulation, in which macrophages play a central pathogenic role. Macrophages accumulate extensively in RA synovium, and their abundance and functional phenotypes are correlated with disease activity and severity. Disturbed macrophage polarization is a key feature of RA progression, characterized by an increased proportion of classically activated (M1) macrophages and a reduced proportion of alternatively activated (M2) macrophages. M1 macrophages produce pro-inflammatory mediators that sustain synovial inflammation and contribute to progressive joint damage. Accumulating evidence indicates that immune cell functions are closely linked to metabolic programs. The synovial microenvironment in RA is marked by hypoxia, acidosis, and nutrient limitation, which lead to substantial metabolic reprogramming during macrophage polarization. Importantly, metabolic changes occur not merely secondary to polarization but actively shape the phenotypic transition of macrophages. In this review, we summarize current evidence on how dysregulation of glucose, lipid, and amino acid metabolism regulates the phenotype switching of macrophages in RA. We discuss the roles of key metabolic enzymes and intermediates in macrophage polarization, consider the diagnostic potential of metabolic biomarkers, and highlight therapeutic opportunities targeting metabolic pathways, thereby resolving macrophage imbalance and improving RA outcomes.

PMID:42312387 | DOI:10.1002/art.70253