Bao Yi, Ledderose Carola, Graf Amelie F, Brix Bianca, Birsak Theresa, Lee Albert, Zhang Jingping, Junger Wolfgang G
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 Ludwig Boltzmann Institute for Traumatology, Vienna A-1200, Austria
J Cell Biol. 2015 Sep 28;210(7):1153-64. doi: 10.1083/jcb.201503066.
Neutrophils use chemotaxis to locate invading bacteria. Adenosine triphosphate (ATP) release and autocrine purinergic signaling via P2Y2 receptors at the front and A2a receptors at the back of cells regulate chemotaxis. Here, we examined the intracellular mechanisms that control these opposing signaling mechanisms. We found that mitochondria deliver ATP that stimulates P2Y2 receptors in response to chemotactic cues, and that P2Y2 receptors promote mTOR signaling, which augments mitochondrial activity near the front of cells. Blocking mTOR signaling with rapamycin or PP242 or mitochondrial ATP production (e.g., with CCCP) reduced mitochondrial Ca(2+) uptake and membrane potential, and impaired cellular ATP release and neutrophil chemotaxis. Autocrine stimulation of A2a receptors causes cyclic adenosine monophosphate accumulation at the back of cells, which inhibits mTOR signaling and mitochondrial activity, resulting in uropod retraction. We conclude that mitochondrial, purinergic, and mTOR signaling regulates neutrophil chemotaxis and may be a pharmacological target in inflammatory diseases.
中性粒细胞利用趋化作用来定位入侵的细菌。三磷酸腺苷（ATP）的释放以及通过细胞前端的P2Y2受体和后端的A2a受体进行的自分泌嘌呤能信号传导调节趋化作用。在此，我们研究了控制这些相反信号传导机制的细胞内机制。我们发现，线粒体响应趋化信号传递ATP，刺激P2Y2受体，并且P2Y2受体促进mTOR信号传导，从而增强细胞前端附近的线粒体活性。用雷帕霉素或PP242阻断mTOR信号传导或抑制线粒体ATP生成（例如用CCCP）会减少线粒体Ca(2+)摄取和膜电位，并损害细胞ATP释放和中性粒细胞趋化作用。A2a受体的自分泌刺激导致细胞后端环磷酸腺苷积累，抑制mTOR信号传导和线粒体活性，导致尾足回缩。我们得出结论，线粒体、嘌呤能和mTOR信号传导调节中性粒细胞趋化作用，可能是炎症性疾病的药理学靶点。
