MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation
MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation
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DOI：
10.1073/pnas.1524292113
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发表时间：
2016-06-07
影响因子：
11.1
通讯作者：
Tabas, Ira
中科院分区：
文献类型：
--
作者：
Cai, Bishuang;Thorp, Edward B.;Tabas, Ira
急性炎症反应需要协调的解决方案，以防止过度炎症，修复附带损伤，并恢复组织稳态，这种反应的失败有助于许多慢性炎症性疾病的病理学。消退部分由长链脂肪酸衍生的脂质介质介导，称为特化促消退介质（SPM）。然而，在炎症反应过程中SPM是如何调节的，以及这个过程在炎症性疾病中是如何出错的，目前还知之甚少。我们现在表明，通过Mer原癌基因酪氨酸激酶（MerTK）受体在培养的巨噬细胞和无菌炎症在体内促进SPM生物合成的机制，涉及一个关键的SPM生物合成酶，5-脂氧合酶的细胞质：核的比例增加。MerTK的这种作用与无菌性腹膜炎的消退有关，并且在缺血-再灌注（I/R）损伤后，与循环SPM增加和远端器官炎症减少有关。MerTK在炎症条件下对ADAM金属肽酶结构域17（ADAM 17）介导的细胞表面切割敏感，但功能意义尚不清楚。我们在这里表明，SPM生物合成增加，炎症消退在一个新的小鼠模型中得到改善，其中内源性MerTK被替换为抗切割的基因工程变体（Mertk（CR））。Mertk（CR）小鼠在I/R后也具有增加的SPM循环水平和较少的肺损伤。因此，炎症期间MerTK裂解限制SPM生物合成和消退反应。这些发现有助于我们理解SPM合成在炎症反应期间是如何调节的，并提出了新的治疗途径，以提高在有缺陷的分辨率促进疾病进展的环境中的分辨率。
The acute inflammatory response requires a coordinated resolution program to prevent excessive inflammation, repair collateral damage, and restore tissue homeostasis, and failure of this response contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated in part by long-chain fatty acid-derived lipid mediators called specialized proresolving mediators (SPMs). However, how SPMs are regulated during the inflammatory response, and how this process goes awry in inflammatory diseases, are poorly understood. We now show that signaling through the Mer proto-oncogene tyrosine kinase (MerTK) receptor in cultured macrophages and in sterile inflammation in vivo promotes SPM biosynthesis by a mechanism involving an increase in the cytoplasmic: nuclear ratio of a key SPM biosynthetic enzyme, 5-lipoxygenase. This action of MerTK is linked to the resolution of sterile peritonitis and, after ischemia-reperfusion (I/R) injury, to increased circulating SPMs and decreased remote organ inflammation. MerTK is susceptible to ADAM metallopeptidase domain 17 (ADAM17)-mediated cell-surface cleavage under inflammatory conditions, but the functional significance is not known. We show here that SPM biosynthesis is increased and inflammation resolution is improved in a new mouse model in which endogenous MerTK was replaced with a genetically engineered variant that is cleavage-resistant (Mertk(CR)). Mertk(CR) mice also have increased circulating levels of SPMs and less lung injury after I/R. Thus, MerTK cleavage during inflammation limits SPM biosynthesis and the resolution response. These findings contribute to our understanding of how SPM synthesis is regulated during the inflammatory response and suggest new therapeutic avenues to boost resolution in settings where defective resolution promotes disease progression.