Lyn is a redox sensor that mediates leukocyte wound attraction in vivo.
Lyn is a redox sensor that mediates leukocyte wound attraction in vivo.
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DOI：
10.1038/nature10632
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发表时间：
2011-11-20
期刊：
影响因子：
64.8
通讯作者：
Huttenlocher, Anna
中科院分区：
文献类型：
--
作者：
Yoo, Sa Kan;Starnes, Taylor W.;Deng, Qing;Huttenlocher, Anna
组织损伤会导致白细胞的快速募集。创伤和肿瘤是一种未愈合的伤口，通过NADPH氧化酶(NOX)产生过氧化氢(H_2O_2)，细胞外的H_2O_2介导白细胞，特别是天然免疫的第一反应者，中性粒细胞，募集到受损组织中。然而，目前尚不清楚中性粒细胞使用什么传感器来检测伤口的氧化还原状态。在这里，我们确定了Src家族激酶(SFK)Lyn是一种氧化还原感受器，它介导中性粒细胞在斑马鱼幼体伤口处的初始募集。中性粒细胞中LYN的激活依赖于组织损伤后创面来源的过氧化氢，抑制LYN可以减少中性粒细胞在伤口中的募集。抑制SFK也破坏了H_2O_2介导的原代人中性粒细胞的趋化作用。体外分析证实，一个半胱氨酸残基C466负责直接氧化介导的LYN激活。此外，与野生型Lyn和半胱氨酸突变体的转基因组织特异性重组表明，Lyn C466在体内对中性粒细胞创伤反应和下游信号转导具有重要作用。据我们所知，这是第一次鉴定出在多细胞生物体中介导白细胞创伤吸引的生理性氧化还原感受器。
Tissue wounding induces the rapid recruitment of leukocytes. Wounds and tumors, a type of “unhealed wound”, generate hydrogen peroxide (H2O2) through a NADPH oxidase (NOX) and the extracellular H2O2 mediates recruitment of leukocytes, particularly first responders of innate immunity, neutrophils, to injured tissue. However, it is not known what sensor neutrophils use to detect the redox state at wounds. Here we identify the Src family kinase (SFK) Lyn as a redox sensor that mediates initial neutrophil recruitment to wounds in zebrafish larvae. Lyn activation in neutrophils is dependent on wound-derived H2O2 following tissue injury and inhibition of Lyn attenuates neutrophil wound recruitment. Inhibition of SFKs also disrupted H2O2-mediated chemotaxis of primary human neutrophils. In vitro analysis identified a single cysteine residue, C466, as being responsible for direct oxidation-mediated activation of Lyn. Furthermore, transgenic tissue-specific reconstitution with wild-type Lyn and a cysteine mutant revealed that Lyn C466 is important for the neutrophil wound response and downstream signaling in vivo. This is the first identification, to our knowledge, of a physiological redox sensor that mediates leukocyte wound attraction in multicellular organisms.
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影响因子：
2.9
作者：
Mathias, Jonathan R.;Dodd, M. Ernest;Walters, Kevin B.;Yoo, Sa Kan;Ranheim, Erik A.;Huttenlocher, Anna
通讯作者：
Huttenlocher, Anna
影响因子：
5.3
作者：
Giannoni, E;Buricchi, F;Chiarugi, P
通讯作者：
Chiarugi, P
影响因子：
4.8
作者：
Abe, J;Takahashi, M;Berk, BC
通讯作者：
Berk, BC
影响因子：
32.4
作者：
NISHIZUMI, H;TANIUCHI, I;YAMAMOTO, T
通讯作者：
YAMAMOTO, T
影响因子：
3.4
作者：
Bienert, Gerd P.;Schjoerring, Jan K.;Jahn, Thomas P.
通讯作者：
Jahn, Thomas P.