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  3. Dorsal root ganglion macrophages mediate osteoarthritis pain via disruption of sensory neuron perineuronal nets

Dorsal root ganglion macrophages mediate osteoarthritis pain via disruption of sensory neuron perineuronal nets

  • Brain Behav Immun. 2026 Mar 27:136:106567. doi: 10.1016/j.bbi.2026.106567.
Fengrun Sun 1,  Xiaofen Tian 2,  Zhe Li 3,  Ning Yu 4,  Huamei Cai 3,  Ziqi Fu 3,  Liang Peng 5,  Jing Zhao 6,  Chao Ma 7,  Tao Wang 8,  Xiaowen Liu 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Human Anatomy, Histology and Embryology, Neuroscience Center, Joint Laboratory of Anesthesia and Pain, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.
  • 2 State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Human Anatomy, Histology and Embryology, Neuroscience Center, Joint Laboratory of Anesthesia and Pain, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China; Department of Anatomy, Key Laboratory of Human Brain Bank for Functions and Diseases of Department of Education of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China.
  • 3 Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China; China-Japan Friendship Hospital, Institute of Clinical Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 4 State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Human Anatomy, Histology and Embryology, Neuroscience Center, Joint Laboratory of Anesthesia and Pain, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China; Department of Neurology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Electronic address: [email protected].
  • 5 Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, China.
  • 6 Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China.
  • 7 State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Human Anatomy, Histology and Embryology, Neuroscience Center, Joint Laboratory of Anesthesia and Pain, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China; National Human Brain Bank for Development and Function, Beijing, China; Chinese Institute for Brain Research, Beijing, China. Electronic address: [email protected].
  • 8 State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Human Anatomy, Histology and Embryology, Neuroscience Center, Joint Laboratory of Anesthesia and Pain, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China. Electronic address: [email protected].
  • 9 Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China. Electronic address: [email protected].
PMID: 41905490 DOI: 10.1016/j.bbi.2026.106567
Abstract

Osteoarthritis (OA) is a widespread joint disease marked by progressive degeneration and chronic joint pain, but effective analgesic therapies are lacking. This study investigated the role of dorsal root ganglion (DRG) macrophages in mediating OA pain, focusing on their effect on perineuronal nets (PNNs) surrounding sensory neurons. In a mono-iodoacetate (MIA)-induced OA model, disruption of PNNs in the DRG, reflected by reduced WFA-labeled PNNs, coincided with mechanical allodynia, thermal hyperalgesia, and reduced weight bearing. Disruption of PNNs via chondroitinase ABC (chABC) or genetic knockdown of Acan worsened pain and increased spontaneous and mechanically-evoked activity of C-fibers. Conversely, macrophage-specific ablation preserved PNNs and alleviated pain. Mechanistically, DRG macrophages were activated via IL 33/ST2 signaling and were associated with reduced PNN integrity. Targeting ST2 in macrophages preserved PNN integrity, reduced macrophage activation, and significantly relieved OA pain. Our results support macrophage-mediated PNN disruption as a key mechanism in OA pain and propose the IL-33/ST2 axis may represent a potential therapeutic target.

Keywords

Interleukin-33, ST2 receptor; Macrophage; Osteoarthritis pain; Perineuronal nets.

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