PDF(Pubmed)
Abstract：
Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene was Sulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generated Sulf2+/- bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloid Sulf2+/- chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic and in vitro analyses indicated that Sulf2 deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL6. This establishes that dynamic remodeling of HS by Sulf2 limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology.
摘要：
硫酸乙酰肝素（HS）蛋白聚糖是细胞对可溶性介质如趋化因子反应的重要调节因子，细胞因子和生长因子。我们分析了编码HS核心蛋白的基因表达的变化，巨噬细胞极化过程中的生物合成酶和修饰剂，并发现最受高度调节的基因是Sulf2，一种细胞外HS6-O-硫酸酯酶，在对促炎刺激的反应中明显下调。然后，我们产生了Sulf2+/-骨髓嵌合小鼠，并检查了抗原诱导的关节炎中的炎症反应，作为类风湿性关节炎的模型。髓样Sulf2+/-嵌合体的炎症消退受损，关节肿胀升高，滑膜组织中促关节炎Th17细胞的丰度增加。转录组学和体外分析表明，Sulf2缺乏增加了骨髓源性巨噬细胞中的I型干扰素信号，导致Th17诱导细胞因子IL6的表达升高。这表明Sulf2对HS的动态重塑限制了巨噬细胞中的I型干扰素信号传导，因此可以防止Th17驱动的病理学。
