The vicious cycle from inflammation to pyroptosis: the core role of macrophage polarization imbalance in the pathogenesis of knee osteoarthritis.

Knee osteoarthritis (KOA) is a chronic degenerative joint disease characterized by cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovial inflammation. Emerging evidence indicates that immune-inflammatory responses, particularly macrophage polarization and pyroptosis, play central roles in KOA pathogenesis. In the synovial microenvironment, macrophages exhibit functional heterogeneity beyond the classical M1/M2 paradigm, with M1-like macrophages predominating and promoting pro-inflammatory signaling through metabolic and epigenetic reprogramming. Concurrently, M2-like macrophages are reduced and functionally impaired, failing to resolve inflammation or support tissue repair. Pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasomes and Gasdermin D (GSDMD), is significantly activated in KOA synovium. M1 macrophages display heightened susceptibility to pyroptosis, releasing IL-1β, IL-18, and damage-associated molecular patterns (DAMPs), which further reinforce M1 polarization and synovial inflammation, forming a self-amplifying "inflammation-pyroptosis-re-inflammation" loop. This maladaptive feedback between macrophage polarization and pyroptosis drives chronic synovitis, cartilage matrix degradation, subchondral bone abnormalities, and persistent pain. Targeting key nodes of this network, including NLRP3, caspase-1, GSDMD, HMGB1/RAGE, and macrophage metabolic pathways, may offer novel therapeutic strategies for KOA. Understanding the interplay between macrophage heterogeneity and pyroptotic signaling provides a mechanistic framework for precision interventions aimed at restoring immune homeostasis and mitigating joint degeneration in KOA.