Harasymowicz Natalia S, Harissa Zainab, Rashidi Neda, Lenz Kristin, Tang Ruhang, Guilak Farshid
Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA; Shriners Hospitals for Children, St. Louis, MO, USA; Center of Regenerative Medicine, Washington University, St. Louis, MO, USA; Department of Orthopaedic Surgery Operations University of Utah, Salt Lake City, UT, USA; Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.
Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA; Shriners Hospitals for Children, St. Louis, MO, USA; Center of Regenerative Medicine, Washington University, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO, USA.
Ann Rheum Dis. 2025 Jun;84(6):1033-1044. doi: 10.1016/j.ard.2025.03.001. Epub 2025 Apr 4.
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.
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.
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.
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.
免疫细胞的异质性和表型调控着许多生理和病理过程。最近的证据表明，免疫细胞在骨关节炎（OA）的进展中起关键作用。我们推测，损伤和肥胖这两个OA的主要危险因素，会影响滑膜的免疫表型，滑膜是关节中免疫细胞的主要储存库。
我们使用单细胞转录组学、免疫分析、转基因小鼠模型和遗传命运图谱方法，对膝关节囊中多种免疫细胞群体的存在和命运进行了表征。
我们发现，关节损伤和肥胖分别及协同改变滑膜囊的结构、细胞和分子特征。我们观察到肥胖动物中巡逻单核细胞较少，并且发现与对照动物相比，肥胖动物在关节损伤后的前3天，促炎单核细胞衍生的巨噬细胞流入量显著更高。我们还发现，内侧半月板手术失稳3天后，形成屏障的滑膜衬里巨噬细胞显著减少，在OA晚期，其数量在正常体重小鼠中显著恢复，但在肥胖小鼠中未恢复。最后，我们表征了其他免疫细胞亚型的存在和变化，包括T细胞、B细胞、肥大细胞和中性粒细胞，以及与损伤和肥胖相关的局部滑液细胞因子。
我们的数据显示，损伤和肥胖分别及协同导致滑膜免疫格局失调，为它们在OA发病机制中的作用提供了新的见解。
