Injury and obesity differentially and synergistically induce dysregulation of synovial immune cells in osteoarthritis

Objectives: The heterogeneity and phenotype of immune cells orchestrate many physiologic and pathologic processes. Recent evidence suggests that immune cells play critical roles in the progression of osteoarthritis (OA). We hypothesised that injury and obesity, two major risk factors for OA, affect the immunophenotype of the synovium, the primary reservoir of immune cells in the joint. Methods: Using single-cell transcriptomics, immunoprofiling, transgenic mouse models, and genetic fate mapping methods, we characterised the presence and fate of multiple populations of immune cells found in the knee joint capsule. Results: We found that joint injury and obesity differentially and synergistically alter the architectural, cellular, and molecular profiles of the synovial capsule. We observed fewer patrolling monocytes in obese animals and found a significantly higher influx of proinflammatory monocyte-derived macrophages in the first 3 days after joint injury in obese compared with that in control animals. We also showed a significant loss of barrier-forming synovial lining macrophages 3 days after destabilisation of medial meniscus surgery, with a significant restoration of their numbers in normal weight but not in obese mice in advanced stages of OA. Finally, we characterised the presence and changes of other immune cell subtypes, including T, B, and mast cells and neutrophils, as well as local synovial fluid cytokines associated with injury and obesity. Conclusions: Our data revealed that injury and obesity independently and synergistically contribute to the dysregulation of the synovial immune landscape, providing new insight into their role in the pathogenesis of OA.