High Mobility Group Protein B1 Promotes Interferon Regulatory Factor 1 SUMOylation to Prime Trained Immunity of Circulating Monocytes and Aggravate the Progressive Synovial Inflammation in Knee Osteoarthritis

  • Research (Wash D C). 2026 May 14:9:1243. doi: 10.34133/research.1243.
Lishi Jie  1  2 ,  Jun Mao  1  2  3 ,  Li Zhang  4 ,  Houyu Fu  1  2 ,  Xiaochen Li  1  2  3 ,  Taiyang Liao  1  2 ,  Yibao Wei  1  2 ,  Deren Liu  1  2 ,  Jiaojiao Du  5 ,  Peng Wu  1  2  3 ,  Songjiang Yin  1  2  3 ,  Nongshan Zhang  1  2  3 ,  Meng Cao  5 ,  Peimin Wang  1  2  3
Affiliations
  • 1. Department of Orthopaedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210023, Jiangsu, China.
  • 2. Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210023, Jiangsu, China.
  • 3. Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing 210023, Jiangsu, China.
  • 4. Department of Traditional Chinese Orthopedics, Zhongda Hospital, Southeast University, Nanjing 210023, Jiangsu, China.
  • 5. Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.
PMID: 42146764 DOI: 10.34133/research.1243
Abstract

Knee osteoarthritis (KOA) is clinically characterized by recurrent and progressively worsening episodes; however, its underlying pathological mechanisms remain incompletely understood. Phenotypic changes and the specific migration of circulating monocytes may be key factors contributing to the recurrence and progressive exacerbation of synovial inflammation in KOA. In this study, we report a specific subtype of circulating monocytes in KOA that highly express interleukin 1A (IL1A), IL1R1, tumor necrosis factor, CXCL12, CXCL3, CXCL2, CCL20, and G0S2. These monocytes exhibit a trained immune phenotype, and their CXCR4-dependent migration to the synovium exacerbates synovial inflammation. HMGB1 (high mobility group protein B1) primes the trained immunity of this subtype, resulting in increased chromatin accessibility, and the transcriptional storage of multiple proinflammatory factors enables them to exhibit a more positive inflammatory response when restimulated by HMGB1. In addition, we find that MyD88, downstream of HMGB1, recruits cytoplasmic interferon regulatory factor 1 to the nucleus and then stabilizes interferon regulatory factor 1 in chromatin through SUMOylation of tripartite motif containing 28 to exert transcriptional activity and epigenetic enhancement of proinflammatory factor expression. Finally, we found that KOA inflammation was effectively attenuated by blocking HMGB1. Taken together, this study reveals the mechanism by which trained immunity of circulating monocytes promotes the progression of synovial inflammation, supporting a future therapeutic approach in the management of KOA.

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