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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月21日

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  • Xin Du,
  • Feng Li,
  • Yebin Deng,
  • Yuheng He,
  • Chao Song,
  • Li Peng

摘要

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.