Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis.
Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis.
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DOI：
10.1186/s13075-016-0973-6
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发表时间：
2016-03-31
影响因子：
4.9
通讯作者：
Reedquist KA
中科院分区：
文献类型：
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作者：
Garcia S;Hartkamp LM;Malvar-Fernandez B;van Es IE;Lin H;Wong J;Long L;Zanghi JA;Rankin AL;Masteller EL;Wong BR;Radstake TR;Tak PP;Reedquist KA
CSF-1或IL-34刺激CSF 1 R促进巨噬细胞分化、活化和破骨细胞生成，并且CSF 1 R的药理学抑制在关节炎动物模型中是有益的。本研究的目的是确定CSF-1和IL-34信号转导对RA中CSF 1 R的相对贡献。应用免疫组织化学和数字图像分析技术检测15例生物学初治类风湿关节炎（RA）、15例银屑病关节炎（PsA）和7例骨关节炎（OA）患者滑膜组织中CSF-1和IL-34的表达。通过FACS分析和定量PCR评估CSF-1和IL-34分化的人巨噬细胞中的基因表达。将RA滑膜外植体与CSF-1、IL-34、对照抗体（Ab）或靶向CSF-1、IL-34或CSF 1 R的中和/阻断Ab孵育。在鼠胶原诱导的关节炎（CIA）中检查CSF 1 R阻断Ab的作用。CSF-1（也称为M-CSF）和IL-34在RA和PsA滑膜组织中的表达相似，但在对照组中较低（P < 0.05）。CSF-1在滑膜下层中表达，IL-34在下层和内膜内层中表达。CSF-1和IL-34差异调节巨噬细胞中336个炎症相关基因中17个的表达，包括趋化因子、细胞外基质成分和基质金属蛋白酶。外源性CSF-1或IL-34，或其独立的中和，对RA滑膜外植体IL-6的产生没有影响。抗CSF 1 R Ab显著降低RA滑膜外植体中IL-6和其他炎性介质的产生，以及CIA中的爪肿胀和关节破坏。同时抑制CSF 1 R与CSF-1和IL-34的相互作用可抑制RA滑膜组织的炎症活化和CIA的病理学，这表明RA的新治疗策略。本文的在线版本（doi：10.1186/s13075-016-0973-6）包含补充材料，可供授权用户使用。
CSF-1 or IL-34 stimulation of CSF1R promotes macrophage differentiation, activation and osteoclastogenesis, and pharmacological inhibition of CSF1R is beneficial in animal models of arthritis. The objective of this study was to determine the relative contributions of CSF-1 and IL-34 signaling to CSF1R in RA. CSF-1 and IL-34 were detected by immunohistochemical and digital image analysis in synovial tissue from 15 biological-naïve rheumatoid arthritis (RA) , 15 psoriatic arthritis (PsA) and 7 osteoarthritis (OA) patients . Gene expression in CSF-1- and IL-34-differentiated human macrophages was assessed by FACS analysis and quantitative PCR. RA synovial explants were incubated with CSF-1, IL-34, control antibody (Ab), or neutralizing/blocking Abs targeting CSF-1, IL-34, or CSF1R. The effect of a CSF1R-blocking Ab was examined in murine collagen-induced arthritis (CIA). CSF-1 (also known as M-CSF) and IL-34 expression was similar in RA and PsA synovial tissue, but lower in controls (P < 0.05). CSF-1 expression was observed in the synovial sublining, and IL-34 in the sublining and the intimal lining layer. CSF-1 and IL-34 differentially regulated the expression of 17 of 336 inflammation-associated genes in macrophages, including chemokines, extra-cellular matrix components, and matrix metalloproteinases. Exogenous CSF-1 or IL-34, or their independent neutralization, had no effect on RA synovial explant IL-6 production. Anti-CSF1R Ab significantly reduced IL-6 and other inflammatory mediator production in RA synovial explants, and paw swelling and joint destruction in CIA. Simultaneous inhibition of CSF1R interactions with both CSF-1 and IL-34 suppresses inflammatory activation of RA synovial tissue and pathology in CIA, suggesting a novel therapeutic strategy for RA. The online version of this article (doi:10.1186/s13075-016-0973-6) contains supplementary material, which is available to authorized users.