Oxidation of methionine 63 and 83 regulates the effect of S100A9 on the migration of neutrophils in vitro
Oxidation of methionine 63 and 83 regulates the effect of S100A9 on the migration of neutrophils in vitro
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DOI：
10.1189/jlb.0706433
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发表时间：
2007-03-01
影响因子：
5.5
通讯作者：
Palefsky, Joel M.
中科院分区：
文献类型：
--
作者：
Sroussi, Herve Y.;Berline, Jennifer;Palefsky, Joel M.
钙结合蛋白S100A8和S100A9及其异源复合物钙卫蛋白是人中性粒细胞中丰富的胞浆成分，由粘膜上皮组成性表达。并与表皮角质形成细胞引起的炎症有关。S100A8和S100A9是多效性蛋白，参与白细胞迁移的调节。本研究旨在研究S100A9对中性粒细胞迁移的影响，并探讨其调节机制。基于先前的S100A8结果，我们假设S100A9排斥中性粒细胞，并且S100A9的氧化调节该功能。使用标准的Transwell趋化性测定和定点突变，我们表明，S100A9对外周血中性粒细胞产生化学排斥（趋除）作用，这种作用被S100A9的氧化所消除。蛋氨酸63和83取代丙氨酸后，S100A9保持其趋避活性，即使在抑制性氧化条件下。总之，这些数据表明，S100A9作为一个分子开关，通过氧化物种保守的甲硫氨酸残基调节炎症的氧化控制。在健康的粘膜组织中，上皮细胞表达S100A9可用于抑制白细胞募集。然而，氧化应激的条件，包括感染和过度生长的机会致病菌，可能会废除这种活性的中和S100A9作为其氧化改变的结果。
The calcium-binding proteins S100A8 and S100A9 and their heterocomplex calprotectin are abundant cytosolic constituents in human neutrophils, constitutively expressed by mucosal epithelium. and in association with inflammation by epidermal keratinocytes. S100A8 and S100A9 are pleiotropic proteins, which partake in the regulation of leukocyte migration. This study was designed to investigate the effect of S100A9 on neutrophil migration and to explore the mechanisms that regulate this effect. Based on previous results with S100A8, we hypothesized that S100A9 repels neutrophils and that oxidation of S100A9 regulates this function. Using standard Transwell chemotaxis assays and site-directed mutagenesis, we show that S100A9 exerts a chemo-repulsive (fugetactic) effect on peripheral neutrophils, an effect abolished by oxidation of S100A9. After substitution of methionine 63 and 83 for alanine, S100A9 maintained its fugetaxis activity, even in inhibitory, oxidative conditions. Together, the data suggest that S100A9 serves as a molecular switch for oxidative control of inflammation regulated by the oxidation of species-conserved methionine residues. In healthy mucosal tissue, expression of S100A9 by the epithelium may serve to inhibit leukocyte recruitment. However, conditions of oxidative stress, including infection and overgrowth of opportunistic pathogens, may abrogate this activity by neutralizing S100A9 as a result of its oxidative alteration.