Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Nat Commun. 2017 May 12;8:15196. doi: 10.1038/ncomms15196.
Circulating neutrophils must avoid premature activation to prevent tissue injury. The leukocyte adhesion receptor L-selectin forms bonds with P-selectin glycoprotein ligand-1 (PSGL-1) on other leukocytes and with peripheral node addressin (PNAd) on high endothelial venules. Mechanical forces can strengthen (catch) or weaken (slip) bonds between biological molecules. How these mechanochemical processes influence function in vivo is unexplored. Here we show that mice expressing an L-selectin mutant (N138G) have altered catch bonds and prolonged bond lifetimes at low forces. Basal lymphocyte homing and neutrophil recruitment to inflamed sites are normal. However, circulating neutrophils form unstable aggregates and are unexpectedly primed to respond robustly to inflammatory mediators. Priming requires signals transduced through L-selectin N138G after it engages PSGL-1 or PNAd. Priming enhances bacterial clearance but increases inflammatory injury and enlarges venous thrombi. Thus, L-selectin mechanochemistry limits premature activation of neutrophils. Our results highlight the importance of probing how mechanochemistry functions in vivo.
循环中的中性粒细胞必须避免过早激活，以防止组织损伤。白细胞黏附受体 L-选择素与其他白细胞上的 P 选择素糖蛋白配体-1（PSGL-1）和高内皮静脉上的外周节点地址素（PNAd）形成键。机械力可以增强（捕获）或削弱（滑动）生物分子之间的键。这些机械化学过程如何影响体内功能尚未可知。在这里，我们表明表达 L-选择素突变体（N138G）的小鼠具有改变的捕获键，并且在低力下键的寿命延长。基础淋巴细胞归巢和中性粒细胞募集到炎症部位是正常的。然而，循环中的中性粒细胞形成不稳定的聚集体，出乎意料地被预先激活，对炎症介质产生强烈反应。引发需要通过 L-选择素 N138G 传递信号，该信号在与 PSGL-1 或 PNAd 结合后传递。引发增强了细菌清除，但增加了炎症损伤并扩大了静脉血栓形成。因此，L-选择素的机械化学限制了中性粒细胞的过早激活。我们的结果强调了探究机械化学在体内如何发挥作用的重要性。
