Increased Galectin-9 Levels Correlate with Disease Activity in Patients with DMARD-Naïve Rheumatoid Arthritis and Modulate the Secretion of MCP-1 and IL-6 from Synovial Fibroblasts.
Increased Galectin-9 Levels Correlate with Disease Activity in Patients with DMARD-Naïve Rheumatoid Arthritis and Modulate the Secretion of MCP-1 and IL-6 from Synovial Fibroblasts.
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背景资料：成纤维细胞样滑膜细胞（FLS）是类风湿性滑膜炎扩张性生长和侵袭性的重要介质，而富含成纤维细胞的寡免疫病理型患者对目前批准的抗风湿药物反应较差。半乳糖凝集素-9（Gal-9）已被报道直接调节类风湿性关节炎（RA）FLS，并保持促炎和抗炎特性。本研究的目的是评估Gal-9在RA中的临床和致病方面，结合国家患者队列和细胞模型。方法：测量新诊断的初治RA患者（n = 98）血浆中的可溶性Gal-9。采用疾病活动性评分、28关节C反应蛋白（DAS 28 CRP）计数和总Sharp评分连续评价2年内的病程。在患有确定的RA的患者（n = 18）中检查血浆和滑液样品的可溶性Gal-9。建立蛋白质阵列以鉴定细胞外基质（ECM）中的Gal-9结合配偶体。从RA患者中收获的滑液单核细胞（SFMCs）用于获得滑液衍生的FLS（SF-FLS）（n = 7）。从接受关节置换手术的患者（n = 5）中收集膝骨关节炎（OA）患者的FLS。SF-FLS的单培养物（n = 6）和SF-FLS与外周血单核细胞（PBMC）的自体共培养物在有中和性抗Gal-9抗体和没有中和性抗Gal-9抗体的情况下培养（n = 7）。随后通过流式细胞术、MTT测定和ELISA分析单培养物和共培养物。结果：与健康对照组（HC）相比，早期和已建立的RA患者血浆Gal-9水平持续升高。Gal-9的血浆水平与疾病活动性相关，并且在标准治疗中加入TNF抑制剂时不受影响。与相应的血浆样本相比，Gal-9水平在患有晚期疾病的RA患者的滑液中升高。Gal-9粘附于纤维连接蛋白、层粘连蛋白和血小板反应蛋白，而不粘附于ECM蛋白阵列中的间质胶原。在体外，中和Gal-9抗体降低RA FLS和OA FLS的MCP-1和IL-6产生。在自体RA FLS和PBMC的共培养中，Gal-9的中和也降低了MCP-1和IL-6的产生，而不影响炎性FLS的比例。结论：在RA中，早期RA的预处理血浆Gal-9水平升高，并与临床疾病活动相关。尽管早期RA患者的疾病活动评分显著降低，但Gal-9水平仍升高。Gal-9的体外中和降低了RA FLS的炎症亚组中MCP-1和IL-6的产生。总的来说，这些研究结果表明，在RA中的持续过表达的半乳糖-9可以调节滑膜FLS活动，并可能参与在RA的亚临床疾病活动的维护。
Background: Fibroblast-like synoviocytes (FLSs) are essential mediators in the expansive growth and invasiveness of rheumatoid synovitis, and patients with a fibroblastic-rich pauci-immune pathotype respond poorly to currently approved antirheumatic drugs. Galectin-9 (Gal-9) has been reported to directly modulate rheumatoid arthritis (RA) FLSs and to hold both pro- and anti-inflammatory properties. The objective of this study was to evaluate clinical and pathogenic aspects of Gal-9 in RA, combining national patient cohorts and cellular models. Methods: Soluble Gal-9 was measured in plasma from patients with newly diagnosed, treatment-naïve RA (n = 98). The disease activity score 28-joint count C-reactive protein (DAS28CRP) and total Sharp score were used to evaluate the disease course serially over a two-year period. Plasma and synovial fluid samples were examined for soluble Gal-9 in patients with established RA (n = 18). A protein array was established to identify Gal-9 binding partners in the extracellular matrix (ECM). Synovial fluid mononuclear cells (SFMCs), harvested from RA patients, were used to obtain synovial-fluid derived FLSs (SF-FLSs) (n = 7). FLSs from patients suffering from knee Osteoarthritis (OA) were collected from patients when undergoing joint replacement surgery (n = 5). Monocultures of SF-FLSs (n = 6) and autologous co-cultures of SF-FLSs and peripheral blood mononuclear cells (PBMCs) were cultured with and without a neutralizing anti-Gal-9 antibody (n = 7). The mono- and co-cultures were subsequently analyzed by flow cytometry, MTT assay, and ELISA. Results: Patients with early and established RA had persistently increased plasma levels of Gal-9 compared with healthy controls (HC). The plasma levels of Gal-9 were associated with disease activity and remained unaffected when adding a TNF-inhibitor to their standard treatment. Gal-9 levels were elevated in the synovial fluid of established RA patients with advanced disease, compared with corresponding plasma samples. Gal-9 adhered to fibronectin, laminin and thrombospondin, while not to interstitial collagens in the ECM protein array. In vitro, a neutralizing Gal-9 antibody decreased MCP-1 and IL-6 production from both RA FLSs and OA FLSs. In co-cultures of autologous RA FLSs and PBMCs, the neutralization of Gal-9 also decreased MCP-1 and IL-6 production, without affecting the proportion of inflammatory FLSs. Conclusions: In RA, pretreatment plasma Gal-9 levels in early RA were increased and correlated with clinical disease activity. Gal-9 levels remained increased despite a significant reduction in the disease activity score in patients with early RA. The in vitro neutralization of Gal-9 decreased both MCP-1 and IL-6 production in an inflammatory subset of RA FLSs. Collectively these findings indicate that the persistent overexpression of Gal-9 in RA may modulate synovial FLS activities and could be involved in the maintenance of subclinical disease activity in RA.
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影响因子：
4.9
作者：
Bustamante MF;Garcia-Carbonell R;Whisenant KD;Guma M
通讯作者：
Guma M
影响因子：
10.7
作者：
Houzelstein, D;Gonçalves, IR;Poirier, F
通讯作者：
Poirier, F
影响因子：
5.5
作者：
Nielsen, Morten Aagaard;Andersen, Thomas;Deleuran, Bent
通讯作者：
Deleuran, Bent
影响因子：
27.4
作者：
Horslev-Petersen, Kim;Hetland, Merete Lund;Stengaard-Pedersen, Kristian
通讯作者：
Stengaard-Pedersen, Kristian
影响因子：
3.7
作者：
Matsumoto H;Fujita Y;Asano T;Matsuoka N;Temmoku J;Sato S;Yashiro-Furuya M;Yokose K;Yoshida S;Suzuki E;Yago T;Watanabe H;Kawakami A;Migita K
通讯作者：
Migita K