Slit2 Regulates Attractive Eosinophil and Repulsive Neutrophil Chemotaxis through Differential srGAP1 Expression during Lung Inflammation

Directional migration of leukocytes is an essential step in leukocyte trafficking during inflammatory responses. However, the molecular mechanisms governing directional chemotaxis of leukocytes remain poorly understood. The Slit family of guidance cues has been implicated for inhibition of leuocyte migration. We report that Clara cells in the bronchial epithelium secreted Slit2, whereas eosinophils and neutrophils expressed its cell-surface receptor, Robo1. Compared to neutrophils, eosinophils exhibited a significantly lower level of Slit-Robo GTPase-activating protein 1 (srGAP1), leading to activation of Cdc42, recruitment of PI3K to Robo1, enhancment of eotaxin-induced eosinophil chemotaxis, and exaggeration of allergic airway inflammation. Notably, OVA sensitization elicited a Slit2 gradient at so-called bronchus-alveoli axis, with a higher level of Slit2 in the bronchial epithelium and a lower level in the alveolar tissue. Aerosol administration of rSlit2 accelerated eosinophil infiltration, whereas i.v. administered Slit2 reduced eosinophil deposition. In contrast, Slit2 inactivated Cdc42 and suppressed stromal cell-derived factor-1 alpha-induced chemotaxis of neutrophils for inhibiting endotoxin-induced lung inflammation, which were reversed by blockade of srGAP1 binding to Robo1. These results indicate that the newly identified Slit2 gradient at the bronchus-alveoli axis induces attractive PI3K signaling in eosinophils and repulsive srGAP1 signaling in neutrophils through differential srGAP1 expression during lung inflammation. The Journal of Immunology, 2010, 185: 6294-6305.

白细胞的定向迁移是炎症反应期间白细胞运输的关键步骤。然而，调控白细胞定向趋化的分子机制仍知之甚少。导向因子Slit家族已被认为可抑制白细胞迁移。我们报道支气管上皮中的克拉拉细胞分泌Slit2，而嗜酸性粒细胞和中性粒细胞表达其细胞表面受体Robo1。与中性粒细胞相比，嗜酸性粒细胞的Slit - Robo GTP酶激活蛋白1（srGAP1）水平显著较低，从而导致Cdc42激活、PI3K向Robo1募集、嗜酸性粒细胞趋化因子诱导的嗜酸性粒细胞趋化作用增强以及过敏性气道炎症加剧。值得注意的是，卵清蛋白致敏在所谓的支气管 - 肺泡轴上引发Slit2梯度，支气管上皮中的Slit2水平较高，而肺泡组织中的水平较低。重组Slit2气溶胶给药加速嗜酸性粒细胞浸润，而静脉注射Slit2则减少嗜酸性粒细胞沉积。相反，Slit2使Cdc42失活，并抑制基质细胞衍生因子 - 1α诱导的中性粒细胞趋化，从而抑制内毒素诱导的肺部炎症，而阻断srGAP1与Robo1的结合可逆转这些作用。这些结果表明，在肺部炎症期间，新发现的支气管 - 肺泡轴上的Slit2梯度通过srGAP1的差异表达，在嗜酸性粒细胞中诱导吸引性的PI3K信号，在中性粒细胞中诱导排斥性的srGAP1信号。《免疫学杂志》，2010年，185卷：6294 - 6305页