Regulation of macrophage polarization and pyroptosis by 4-methylcatechol alleviates collagen-induced arthritis via Nrf2/HO-1 and NF-κB/NLRP3 signaling pathways

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint deformity and ultimately disability. The metabolite of quercetin, 4-Methylcatechol (4-MC), has been acknowledged for its anti-inflammatory and antioxidant properties; however, the protective effects of 4-MC on RA and its underlying mechanisms remain incompletely elucidated. In a collagen-induced arthritis (CIA) model, we observed that 4-MC effectively mitigated joint inflammation and bone destruction in CIA mice. Additionally, it significantly suppressed the upregulated expression of inflammatory cytokines in synovial tissues. Mechanistically, upon lipopolysaccharide (LPS) stimulation, 4-MC inhibited M1 polarization of macrophages and induced a phenotypic switch from M1 to M2 phenotype, thereby reducing the release of pro-inflammatory cytokines by M1 macrophages while increasing the release of anti-inflammatory cytokines by M2 macrophages. Furthermore, it attenuated LPS/adenosine triphosphate (ATP)-induced pyroptosis in macrophages by downregulating NLRP3 expression levels along with cleaved caspase-1, cleaved IL-1β, and GSDMD-NT expression levels. Notably, our findings revealed that 4-MC exerted inhibitory effects on the NF-κB signaling pathway through specific modulation of the NF-κB complex as well as phosphorylation of the upstream IKK kinase complex. Collectively, these results highlight significant therapeutic potential for utilizing 4-MC in RA treatment.

Keywords: 4-Methylcatechol; Collagen-induced arthritis; Macrophage; Polarization; Pyroptosis.