Arthritis Program, University Health Network, Toronto, ON, Canada.
Krembil Research Institute, University Health Network, Toronto, ON, Canada.
Arthritis Res Ther. 2019 Jan 18;21(1):26. doi: 10.1186/s13075-018-1798-2.
Chronic, low-grade inflammation of the synovium (synovitis) is a hallmark of osteoarthritis (OA), thus understanding of OA immunobiology, mediated by immune effectors, is of importance. Specifically, monocytes/macrophages (MΦs) are known to be abundantly present in OA joints and involved in OA progression. However, different subsets of OA MΦs have not been investigated in detail, especially in terms of their relationship with patient-reported outcome measures (PROMs). We hypothesized that levels of synovial fluid (SF) MΦ subsets are indicative of joint function and quality of life in patients with OA, and can therefore serve as biomarkers and therapeutic targets for OA.
In this cohort study, synovial fluid leukocytes (SFLs, N = 86) and peripheral blood mononuclear cells (n = 53) from patients with knee OA were characterized. Soluble MΦ receptors and chemokine (sCD14, sCD163, CCL2, CX3CL1) levels were detected in SF using immunoassays. Linear models, adjusted for sex, age and body mass index, were used to determine associations between SF MΦs and soluble factors with PROMs (N = 83). Pearson correlation was calculated to determine correlation between MΦ subsets, T cells and soluble factors.
SF MΦs were the most abundant SFLs. Within these, the double-positive CD14CD16-MΦ subset is enriched in knee OA SF compared to the circulation. Importantly, MΦ subset ratios correlated with PROMs, specially stiffness, function and quality of life. Interestingly, the SF CD14CD16-MΦ subset ratio correlated with SF chemokine (C-C motif) ligand 2 (CCL2) levels but not with levels of sCD163 or sCD14; we found no association between PROMs and either SF CCL2, sCD163, sCD14 or CX3CL1 (which was below detection levels). All SF MΦs displayed high levels of HLA-DR, suggesting an activated phenotype. Correlation between OA SF MΦ subsets and activated CD4 T cell subsets suggests modulation of CD4 T cell activation by MΦs.
SF MΦ subsets are associated with knee OA PROMs and display an activated phenotype, which may lead to modulation of CD4 T cell activation. Knee OA SF MΦ subsets could serve as knee OA function biomarkers and as targets of novel therapeutics.
滑膜的慢性、低度炎症（滑膜炎）是骨关节炎（OA）的标志，因此，对免疫效应器介导的 OA 免疫生物学的理解很重要。具体而言，已知单核细胞/巨噬细胞（MΦ）在 OA 关节中大量存在，并参与 OA 进展。然而，OA MΦ 的不同亚群尚未得到详细研究，特别是在与患者报告的结果测量（PROM）的关系方面。我们假设滑液（SF）MΦ 亚群的水平可以反映 OA 患者的关节功能和生活质量，因此可以作为 OA 的生物标志物和治疗靶点。
在这项队列研究中，对膝关节 OA 患者的滑膜液白细胞（SFL，N=86）和外周血单核细胞（n=53）进行了特征分析。使用免疫测定法检测 SF 中的可溶性 MΦ 受体和趋化因子（sCD14、sCD163、CCL2、CX3CL1）水平。使用线性模型，对性别、年龄和体重指数进行调整，以确定 SF MΦ 和可溶性因子与 PROM（N=83）之间的关联。计算 Pearson 相关性以确定 MΦ 亚群、T 细胞和可溶性因子之间的相关性。
SF MΦ 是最丰富的 SFL。在这些细胞中，与循环相比，CD14CD16-MΦ 双阳性亚群在膝 OA SF 中富集。重要的是，MΦ 亚群比值与 PROM 相关，特别是僵硬、功能和生活质量。有趣的是，SF CD14CD16-MΦ 亚群比值与 SF 趋化因子（C-C 基序）配体 2（CCL2）水平相关，但与 sCD163 或 sCD14 水平无关；我们发现 PROM 与 SF CCL2、sCD163、sCD14 或 CX3CL1 之间没有关联（后者低于检测水平）。所有 SF MΦ 均显示高水平的 HLA-DR，表明其呈激活表型。OA SF MΦ 亚群与激活的 CD4 T 细胞亚群之间的相关性表明 MΦ 可调节 CD4 T 细胞的激活。
SF MΦ 亚群与膝关节 OA PROM 相关，并表现出激活表型，这可能导致 CD4 T 细胞的激活受到调节。膝关节 OA SF MΦ 亚群可作为膝关节 OA 功能的生物标志物，并作为新型治疗药物的靶点。
