Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
Osteoarthritis Cartilage. 2020 May;28(5):613-625. doi: 10.1016/j.joca.2020.01.009. Epub 2020 Jan 29.
Monocyte-derived macrophages, as the predominant immune cell type that is increased in inflamed synovium, play a vital role during knee osteoarthritis (KOA) progression. However, the mechanisms underlying the recruitment of circulating monocytes to osteoarthritic knees remain uncertain. Based on previous data obtained from plasma, we investigated the contributions of CCL2, CCL3, CCL4 and their cognate receptors in circulating monocyte chemotaxis and KOA development.
Using flow cytometry staining, we characterized the expression patterns of the chemokine receptors in CD14CD16 circulating monocytes from KOA patients and healthy volunteers. The expression of chemokines in synovial fluids, synovium and cartilage was investigated in KOA patients and in patients without KOA. The role of chemokines and their cognate receptors in the chemotaxis of CD14CD16 circulating monocytes was assessed using chemokine neutralizing antibodies (NA) and receptor antagonists in vitro and in vivo.
The majority of CD14CD16 circulating monocytes were CCR1-and CCR2-positive. CCL2, CCL3 and CCL4 were elevated in synovial fluid of KOA patients compared with that of controls. The most likely source of these chemokines is inflamed synovium and cartilage in the osteoarthritic knee. The CCL3/CCR1 and CCL2/CCR2 axes showed substantial ability to recruit CD14CD16 monocytes in transwell assays. Similar results were confirmed in a mouse model of collagenase-induced KOA (CIA) in which blocking either the CCL3/CCR1 axis or the CCL2/CCR2 axis reduced synovial hyperplasia and F4/80 macrophage infiltration.
Our findings suggested that, analogous to the CCL2/CCR2 axis, CCL3 produced in osteoarthritic knees can chemoattract circulating monocytes to the inflamed synovium through CCR1.
单核细胞衍生的巨噬细胞作为在炎症滑膜中增加的主要免疫细胞类型，在膝骨关节炎（KOA）进展中发挥着重要作用。然而，循环单核细胞募集到骨关节炎膝关节的确切机制尚不清楚。基于之前从血浆中获得的数据，我们研究了趋化因子 CCL2、CCL3、CCL4 及其同源受体在循环单核细胞趋化和 KOA 发展中的作用。
通过流式细胞术染色，我们对 KOA 患者和健康志愿者的循环 CD14CD16 单核细胞中的趋化因子受体表达模式进行了特征描述。在 KOA 患者和无 KOA 患者中，我们研究了趋化因子在滑液、滑膜和软骨中的表达。在体外和体内使用趋化因子中和抗体（NA）和受体拮抗剂评估趋化因子及其同源受体在 CD14CD16 循环单核细胞趋化中的作用。
大多数 CD14CD16 循环单核细胞为 CCR1 和 CCR2 阳性。与对照组相比，KOA 患者的滑液中 CCL2、CCL3 和 CCL4 升高。这些趋化因子的最可能来源是炎症性滑膜和骨关节炎膝关节中的软骨。CCL3/CCR1 和 CCL2/CCR2 轴在 Transwell 测定中显示出募集 CD14CD16 单核细胞的强大能力。在胶原酶诱导的 KOA（CIA）小鼠模型中也证实了类似的结果，其中阻断 CCL3/CCR1 轴或 CCL2/CCR2 轴均可减少滑膜增生和 F4/80 巨噬细胞浸润。
我们的研究结果表明，类似于 CCL2/CCR2 轴，骨关节炎膝关节中产生的 CCL3 可以通过 CCR1 趋化循环单核细胞到炎症滑膜。
