Macrophage lipid metabolism and inflammasome activation in rheumatoid arthritis: emerging mechanisms and therapeutic implications

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, synovial hyperplasia, cartilage destruction, and bone erosion. Within the multicellular RA synovial network, macrophages act as important inflammatory effectors and metabolic sensors whose functional states are shaped by lipid metabolic reprogramming. In RA synovium, impaired cholesterol efflux and altered fatty acid flux remodel membrane lipid composition and lipid-raft-dependent Toll-like receptor (TLR)–NF-κB signaling, thereby enhancing the expression of NOD-like receptor family pyrin domain-containing 3 (NLRP3) and pro-interleukin-1β (pro-IL-1β). Cholesterol overload or crystallization, saturated fatty acid-induced lipotoxicity, mitochondrial and lysosomal injury, mitochondrial reactive oxygen species, ionic imbalance, and lipid peroxidation generate activation-associated signals that lower the threshold for NLRP3 inflammasome activation. Mechanistic studies, largely outside RA, suggest that fatty acid synthase (FASN)-dependent production of palmitate-derived acyl donors may support ZDHHC-mediated NLRP3 palmitoylation, subcellular trafficking, NEK7 interaction, ASC recruitment, and inflammasome assembly. Liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) function as complementary lipid-sensing regulators: LXR mainly controls cholesterol efflux and membrane signaling, whereas PPARs coordinate fatty acid handling, mitochondrial adaptation, efferocytosis, and resolution-associated programs. Activation of the NLRP3–caspase-1 axis promotes IL-1β and IL-18 maturation and gasdermin D-mediated pyroptosis, amplifying macrophage–fibroblast-like synoviocyte crosstalk, immune-cell recruitment, osteoclastogenesis, and structural joint damage. Because direct validation of the complete FASN–palmitoylation–NLRP3 sequence in RA synovial macrophages remains limited, this axis is presented as a testable RA-relevant mechanistic framework rather than an established RA-specific pathway while highlighting potential targets for macrophage-directed immunometabolic intervention.