Inactivation of heparan sulfate 2-O-sulfotransferase accentuates neutrophil infiltration during acute inflammation in mice
Inactivation of heparan sulfate 2-O-sulfotransferase accentuates neutrophil infiltration during acute inflammation in mice
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DOI：
10.1182/blood-2012-03-417139
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发表时间：
2012-08-23
期刊：
影响因子：
20.3
通讯作者：
Esko, Jeffrey D.
中科院分区：
文献类型：
--
作者：
Axelsson, Jakob;Xu, Ding;Esko, Jeffrey D.
炎症部位的中性粒细胞募集和外渗为宿主防御提供了一种机制。我们先前的研究表明，硫酸乙酰肝素是一种硫酸化的糖胺多聚糖，通过选择性灭活内皮细胞中的N-乙酰氨基葡萄糖N-脱乙酰酶-N-磺基转移酶(NDST1)来减少中性粒细胞在小鼠体内的渗透，从而促进中性粒细胞的募集。在这里，我们显示内皮细胞糖醛酸基2-O-磺基转移酶(Hs2st)失活，这是一种作用于NDST1下游的酶，在几种急性炎症模型中导致中性粒细胞募集增加。中性粒细胞在体内和体外流动时滚动速度减慢是导致中性粒细胞浸润增加的部分原因，这与中性粒细胞L-选择素与突变内皮细胞的结合增强有关。Hs2st基因缺失的内皮细胞与巨噬细胞炎性蛋白-2的结合也显著增加。中性粒细胞募集的这些介质的结合增强是由于氨基葡萄糖单元的N-硫酸和6-O-硫酸作用增加而引起的硫酸乙酰肝素结构的改变，以响应糖醛酸残基的2-O-硫酸作用的减少。这种功能获得表型提供了强有力的证据，证明了内皮硫酸肝素在炎症中的重要性，并建议了一种新的酶靶点，用于增强先天性免疫反应。(血。2012；120(8)：1742-1751)
Neutrophil recruitment and extravasation at sites of inflammation provide a mechanism for host defense. We showed previously that heparan sulfate, a type of sulfated glycosaminoglycan, facilitates neutrophil recruitment based on the reduction of neutrophil infiltration in mice in which the overall sulfation of the chains was reduced by selective inactivation of N-acetylglucosamine N-deacetylase-N-sulfotransferase (Ndst1) in endothelial cells. Here we show that inactivation of uronyl 2-O-sulfotransferase in endothelial cells (Hs2st), an enzyme that acts downstream from Ndst1, results in enhanced neutrophil recruitment in several models of acute inflammation. Enhanced neutrophil infiltration resulted in part from reduced rolling velocity under flow both in vivo and in vitro, which correlated with stronger binding of neutrophil L-selectin to mutant endothelial cells. Hs2st-deficient endothelial cells also displayed a striking increase in binding of IL-8 and macrophage inflammatory protein-2. The enhanced binding of these mediators of neutrophil recruitment resulted from a change in heparan sulfate structure caused by increased N-sulfation and 6-O-sulfation of glucosamine units in response to the decrease in 2-O-sulfation of uronic acid residues. This gain-of-function phenotype provides formidable evidence demonstrating the importance of endothelial heparan sulfate in inflammation and suggests a novel enzyme target for enhancing the innate immune response. (Blood. 2012;120(8):1742-1751)