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新发现!让你得痛风的原来是这个东西!

时间:2017-06-20 作者: 痛风防治指南

痛风,是所有关节炎中最痛的一种。

当尿酸析出形成结晶(单钠尿酸盐晶体)时,机体会出现一系列的变化,即急性炎症反应。

虽然大家都知道单钠尿酸盐晶体(MSUs)会激活中性粒细胞(痛风患者关节滑液中数量最多的白细胞种类),但是在发生炎症的关节中,单钠尿酸盐以及促炎介质的共同刺激对中性粒细胞有哪些影响,目前还不得而知。

我们在痛风患者的关节滑液中发现了一种高度表达的蛋白,S100A9。

同时,我们在血管内和血管周围也发现了它的踪影,这表明在中性粒细胞从血管内迁移至发炎的关节时,S100A9蛋白起着重要的作用。

结合功能和信号分析:

我们发现S100A9蛋白增强了氧自由基的生成,同时在中性粒细胞被单钠尿酸盐激活后,促使了中性粒细胞释放白介素-1和白介素-8。 

在人类的中性粒细胞中,S100A9蛋白也能促使单钠尿酸盐激活上游和下游的信号通路,包括动员细胞内钙,酪氨酸磷酸化,蛋白激酶C底物(Akt和p38)的丝氨酸磷酸化。

我们还发现,S100A9蛋白能增加人类白细胞内的糖酵解,意味着这是另一个控制中性粒细胞的机制。

总而言之,我们的研究发现了S100A9蛋白对痛风发病的作用,即机体受到单钠尿酸盐刺激后,S100A9蛋白可以通过控制中性粒细胞起作用,进而引起炎症反应,产生相应的临床症状(如红、肿、热、痛)。


原文:

S100A9 potentiates the activation of neutrophils by the etiological agent of gout, monosodium urate crystals.

J Leukoc Biol. 2017 May 26.

pii: jlb.3MA0117-020R.

doi: 10.1189/jlb.3MA0117-020R.

 

◆ Author

RousseauLS1, Paré G1, Lachhab A1, Naccache PH1,Marceau F1, Tessier P1, Pelletier M2,Fernandes M3.

 

◆ Author information

  1. Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, Ville deQuébec, Québec, Canada.

  2. Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, Ville deQuébec, Québec, Canada martin.pelletier@crchudequebec.ulaval.ca.

  3. Department of Microbiology-InfectiousDiseases and Immunology, Faculty of Medicine, Laval University, Ville deQuébec, Québec, Canada maria.fernandes@crchul.ulaval.ca.


Abstract

———


Gout is one of the most painful types of arthritis that arises when the body mounts an acute inflammatory reactionagainst a crystallized form of uric acid known as monosodium urate crystals(MSUs). Although MSUs are known to activate neutrophils, the most abundantleukocyte 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 aprotein that is highly expressed in the synovium in gout, S100A9. The predominant expression of S100A9 in and around blood vessels suggests it mayprime neutrophils during their migration toward the inflamed joint. Using acombination of functional and signaling assays, we found that S100A9 enhancesthe production of radical oxygen species as well as IL-1 and IL-8 release byhuman neutrophils activated with MSU. Moreover, upstream and downstreamsignaling events activated by MSUs in human neutrophils were also potentiatedby S100A9, including the mobilization of intracellular calcium stores, tyrosinephosphorylation, the serine phosphorylation of PKC substrates, Akt, and p38. Wealso show that S100A9 alone increases glycolysis in human neutrophils, which issuggestive of an additional mechanism through which neutrophils can be primed.Together, our observations indicate a novel way in which S100A9 may contributeto the pathogenesis of gout, by priming neutrophils to respond to MSUs.

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