Neutrophil extracellular traps in rheumatoid arthritis: pathogenic mechanisms and therapeutic potential

作者：Chengliang Mao, Chen-Huan Yu, Song-Lin Jiang, Zhenhua Ying, Xingyi Zhu · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1717671 · 被引用次数：12 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Immune cells in cancer、Rheumatoid Arthritis Research and Therapies

Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by synovial inflammation, joint destruction, and systemic complications, eventually leading to a high rate of disability, but its exact pathogenesis remains unclear. Neutrophil extracellular traps (NETs) are chromatin fibers released by activated neutrophils during infection/inflammation, containing histones, antimicrobial proteins, and granule components. Under physiological conditions, NETs trap pathogens and act as a pivotal anti-infective mechanism of the innate immune response. During the development of RA, NET components act as danger-associated molecular patterns (DAMPs) to activate NLRP3 inflammasomes and the complements in effector lymphocytes, amplifying inflammation; NETs promote the RA-related autoantibody production in B cells, such as anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), fueling autoimmunity, while ACPAs further induce NETosis, creating a vicious feedback loop; NETs facilitate the release of pro-inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α), exacerbating joint damage; finally, NETs activate T cells, dendritic cells, and macrophages via boosting RAGE/TLR9 pathway, thereby driving the proliferation and migration fibroblast-like synoviocytes. Notably, inhibiting NET formation (e.g., FcαRI antibody, celastrol), blocking NET-mediated inflammation (e.g., RAGE/TLR9 antagonists), and clearing NET remnants to break the pathogenic cycle (e.g., PAD enzyme inhibitors, D...