PDF(Pubmed)
Abstract：
One question in lymphocyte homing is how integrins are rapidly activated to enable immediate arrest of fast rolling lymphocytes upon encountering chemokines at target vascular beds given the slow chemokine-induced integrin inside-out activation. Herein we demonstrate that chemokine CCL25-triggered Ca2+ influx induces T cell membrane-proximal external Ca2+ concentration ([Ca2+]ex) drop in 6 s from physiological concentration 1.2 mM to 0.3 mM, a critical extracellular Ca2+ threshold for inducing αLβ2 activation, triggering rapid αLβ2 activation and T cell arrest before occurrence of αLβ2 inside-out activation. Talin knockdown inhibits the slow inside-out activation of αLβ2 but not [Ca2+]ex drop-triggered αLβ2 quick activation. Blocking Ca2+ influx significantly suppresses T cell rolling-to-arrest transition and homing to skin lesions in a mouse psoriasis model, thus alleviating skin inflammation. [Ca2+]ex decrease-triggered rapid integrin activation bridges the gap between initial chemokine stimulation and slow integrin inside-out activation, ensuring immediate lymphocyte arrest and subsequent diapedesis on the right location.
摘要：
淋巴细胞归巢中的一个问题是，鉴于趋化因子诱导的整合素由内而外的缓慢激活，在目标血管床处遇到趋化因子时，整合素如何被快速激活以使快速滚动的淋巴细胞立即停止。在本文中，我们证明趋化因子CCL25触发的Ca2内流诱导T细胞膜近端外部Ca2浓度（[Ca2]ex）在6s内从生理浓度1.2mM下降到0.3mM，诱导αLβ2活化的关键细胞外Ca2+阈值，在发生αLβ2内向外激活之前触发快速αLβ2激活和T细胞停滞。Talin敲低抑制αLβ2的缓慢由内而外的激活，但不抑制[Ca2]外降触发的αLβ2的快速激活。在小鼠牛皮癣模型中，阻断Ca2内流可显着抑制T细胞滚动至停滞的过渡和归巢至皮肤病变，从而缓解皮肤炎症。[Ca2+]ex-decrease-trigeredrequidintegrinactivationbridgethegapbetweeninitialchemokinestimulationandlowintegrininside-outactivation,确保在正确的位置立即停止淋巴细胞和随后的透析。
