S100A9 potentiates the activation of neutrophils by the etiological agent of gout, monosodium urate crystals
S100A9 potentiates the activation of neutrophils by the etiological agent of gout, monosodium urate crystals
复制标题
DOI：
10.1189/jlb.3ma0117-020r
复制
发表时间：
2017-09-01
影响因子：
5.5
通讯作者：
Fernandes, Maria
中科院分区：
文献类型：
--
作者：
Rousseau, Louis-Simon;Pare, Guillaume;Fernandes, Maria
痛风是最痛苦的关节炎之一，当身体对尿酸结晶形式（称为尿酸钠晶体（MSU））产生急性炎症反应时，就会出现痛风。尽管已知 MSU 可以激活中性粒细胞（痛风患者滑液中最丰富的白细胞），但很少有研究调查在发炎关节中同时刺激 MSU 和促炎介质对中性粒细胞的影响。在此，我们重点关注痛风滑膜中高表达的蛋白质 S100A9。 S100A9 在血管内和周围的主要表达表明，它可能在中性粒细胞向发炎关节迁移的过程中启动它们。通过结合功能和信号检测，我们发现 S100A9 可以增强自由基氧的产生以及 MSU 激活的人中性粒细胞的 IL-1 和 IL-8 释放。此外，S100A9 还增强了人中性粒细胞中 MSU 激活的上游和下游信号事件，包括细胞内钙储备的动员、酪氨酸磷酸化、PKC 底物、Akt 和 p38 的丝氨酸磷酸化。我们还表明，S100A9 单独会增加人中性粒细胞的糖酵解，这表明可以启动中性粒细胞的额外机制。总之，我们的观察结果表明，S100A9 可能通过启动中性粒细胞对 MSU 做出反应，从而促进痛风的发病机制。
Gout is one of the most painful types of arthritis that arises when the body mounts an acute inflammatory reaction against a crystallized form of uric acid known as monosodium urate crystals (MSUs). Although MSUs are known to activate neutrophils, the most abundant leukocyte in the synovial fluid of patients with gout, few studies have investigated the effect on neutrophils of the simultaneous stimulation with MSU and proinflammatory mediators in the inflamed joint. Herein, we focused on a protein that is highly expressed in the synovium in gout, S100A9. The predominant expression of S100A9 in and around blood vessels suggests it may prime neutrophils during their migration toward the inflamed joint. Using a combination of functional and signaling assays, we found that S100A9 enhances the production of radical oxygen species as well as IL-1 and IL-8 release by human neutrophils activated with MSU. Moreover, upstream and downstream signaling events activated by MSUs in human neutrophils were also potentiated by S100A9, including the mobilization of intracellular calcium stores, tyrosine phosphorylation, the serine phosphorylation of PKC substrates, Akt, and p38. We also show that S100A9 alone increases glycolysis in human neutrophils, which is suggestive of an additional mechanism through which neutrophils can be primed. Together, our observations indicate a novel way in which S100A9 may contribute to the pathogenesis of gout, by priming neutrophils to respond to MSUs.