HMGB1 promotes IRF1 SUMOylation to prime trained immunity of circulating monocytes and aggravate the progressive synovial inflammation in knee osteoarthritis

Knee osteoarthritis (KOA) is clinically characterized by recurrent and progressively worsening episodes;however, its underlying pathological mechanisms remain incompletely understood. Phenotypic changesand the specific migration of circulating monocytes may be key factors contributing to the recurrenceand progressive exacerbation of synovial inflammation in KOA. In this study, we report a specificsubtype of circulating monocytes in KOA that highly express IL1A, IL1R1, TNF, 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 groupprotein B1) primes the trained immunity of this subtype, resulting in increased chromatin accessibility,and the transcriptional storage of multiple pro-inflammatory factors enables them to exhibit a morepositive inflammatory response when restimulated by HMGB1. In addition, we find that MyD88,downstream of HMGB1, recruits cytoplasmic IRF1 to the nucleus, and then stabilizes IRF1 in chromatinthrough SUMOylation of TRIM28 to exert transcriptional activity and epigenetic enhancement of pro-inflammatory factor expression. Finally, we found that KOA inflammation was effectively attenuated byblocking HMGB1. Taken together, this study reveals the mechanism by which trained immunity ofcirculating monocyte promote the progression of synovial inflammation, support a future therapeuticapproach in the management of KOA.Keywordsknee osteoarthritis; trained immunity; HMGB1; IRF1; SUMOylation; CXCL12; CXCR4