Institut für Physiologie II, Wilhems-Universität Münster, 48149 Münster, Germany.
Sci Signal. 2010 Jul 27;3(132):ra55. doi: 10.1126/scisignal.2000588.
Chemotaxis, the movement of cells along chemical gradients, is critical for the recruitment of immune cells to sites of inflammation; however, how cells navigate in chemotactic gradients is poorly understood. Here, we show that macrophages navigate in a gradient of the chemoattractant C5a through the release of adenosine triphosphate (ATP) and autocrine "purinergic feedback loops" that involve receptors for ATP (P2Y(2)), adenosine diphosphate (ADP) (P2Y(12)), and adenosine (A2a, A2b, and A3). Whereas macrophages from mice deficient in pannexin-1 (which is part of a putative ATP release pathway), P2Y(2), or P2Y(12) exhibited efficient chemotactic navigation, chemotaxis was blocked by apyrase, which degrades ATP and ADP, and by the inhibition of multiple purinergic receptors. Furthermore, apyrase impaired the recruitment of monocytes in a mouse model of C5a-induced peritonitis. In addition, we found that stimulation of P2Y(2), P2Y(12), or adenosine receptors induced the formation of lamellipodial membrane protrusions, causing cell spreading. We propose a model in which autocrine purinergic receptor signaling amplifies and translates chemotactic cues into directional motility.
趋化作用，即细胞沿着化学梯度的运动，对于免疫细胞向炎症部位的募集至关重要；然而，细胞如何在趋化梯度中导航还知之甚少。在这里，我们表明巨噬细胞通过释放三磷酸腺苷 (ATP) 和涉及 ATP（P2Y(2)）、二磷酸腺苷 (ADP)（P2Y(12)）和腺苷受体的自分泌“嘌呤能反馈环”，在趋化因子 C5a 的梯度中导航。而缺乏连接蛋白-1（一种潜在的 ATP 释放途径的一部分）、P2Y(2) 或 P2Y(12) 的小鼠的巨噬细胞表现出有效的趋化性导航，然而，apyrase（一种降解 ATP 和 ADP 的酶）和抑制多种嘌呤能受体则阻断了趋化性。此外，apyrase 还损害了在 C5a 诱导的腹膜炎小鼠模型中单核细胞的募集。此外，我们发现 P2Y(2)、P2Y(12) 或腺苷受体的刺激诱导了片状伪足膜突起的形成，导致细胞伸展。我们提出了一个模型，其中自分泌嘌呤能受体信号放大并将趋化信号转化为定向运动。
