Abstract
BackgroundChronic, 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.MethodsIn 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.ResultsSF MΦs were the most abundant SFLs. Within these, the double-positive CD14+CD16+-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 CD14+CD16+-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.ConclusionSF 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.
Highlights
Chronic, low-grade inflammation of the synovium is a hallmark of osteoarthritis (OA), understanding of OA immunobiology, mediated by immune effectors, is of importance
Use of pain medications is tabulated in Additional file 1: Table S2; and no effects on MΦ subset frequencies in total synovial fluid (SF) MΦs was seen from use of pain medications (Additional file 1: Figure S2)
SF knee OA (KOA) CD14+CD16+ MΦ subset is associated with SF Chemokine ligand 2 (CCL2) levels We investigated whether the level of CCL2, an important MΦ chemoattractant [17] and agonist of CCR2, is associated with the ratios of MΦ subsets from OA SF
Summary
Low-grade inflammation of the synovium (synovitis) is a hallmark of osteoarthritis (OA), understanding of OA immunobiology, mediated by immune effectors, is of importance. Monocytes/ macrophages (MΦs) are known to be abundantly present in OA joints and involved in OA progression. Osteoarthritis (OA) is increasingly considered a chronic, low-grade inflammatory disease with involvement of synovial inflammation (synovitis) [1]. Synovitis promotes an inflammatory environment associated with cartilage degradation [2]. Synovitis predicts OA progression and is associated with pain and cartilage degradation [3, 4]. MΦs from OA synovium produce inflammatory and degradative mediators [6] and ablation of synovial-resident MΦs reduces OA severity in a murine model [7]. There is evidence that MΦs contribute to the OA pathogenesis
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