Authors:

Heer Patel

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About Paper:

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which synovial macrophages sustain joint inflammation and drive progressive tissue damage. Inflammatory macrophage phenotypes are increasingly linked to metabolic reprogramming, particularly a shift toward glycolysis and lactate production, but how these pathways operate in human RA cells remains incompletely defined. This project investigates how a lactate-rich, glycolytic environment shapes inflammatory responses in RA patients - derived macrophages and whether blocking glycolysis can reduce this activation. Peripheral blood mononuclear cells from RA patients were isolated by density-gradient centrifugation and differentiated into monocyte-derived macrophages with granulocyte—macrophage colony-stimulating factor (GM-CSF) to model the synovial compartment. Macrophages were then treated with phosphate-buffered saline (PBS, control) or lactate, with or without a hexokinase-2 inhibitor (HK2i) to limit glycolytic flux. RNA was extracted, converted to cDNA, and analyzed by quantitative PCR to measure pro-inflammatory cytokines and chemokines (e.g., IL1B, IL6, CCL2), interferon-stimulated genes, M1- and M2-associated markers, and transcripts encoding glycolytic and oxidative metabolism enzymes. Preliminary results show that GM-CSF-primed RA macrophages upregulate glycolytic mediators (GLUT1, HK2, LDHA) and downregulate oxidative metabolism genes, consistent with a glycolytic shift. Lactate further increases expression of M1-associated markers and inflammatory cytokines, whereas M2-associated genes are relatively suppressed, indicating a glycolysis-linked, hyper-inflammatory phenotype. In contrast, treatment with HK2i attenuates lactate-induced cytokine expression, partially restores M2-associated markers, and enhances oxidative metabolism transcripts. These findings support the hypothesis that dysregulated glycolytic metabolism reinforces pathogenic macrophage activation in RA and suggest that targeting glycolysis, particularly HK2, may represent a promising metabolic strategy to modulate macrophage-driven synovial inflammation. This project contributes to a growing field of RA immunometabolism by directly testing metabolic control of human RA macrophages. COOH OOOH SO OOSS SSO TH OOO HOC ESOSECHOCOCEC HEE OEOOOCOOCE OOO GFFFDFFFIIDDDIDIDIDIDDIDFDIDDIDIDHHFDDIIIIIHHIDIIIIGD

Source:

University of Illinois Chicago

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Co-authors:

Heer Patel