Priming by chemokines restricts lateral mobility of the adhesion receptor LFA-1 and restores adhesion to ICAM-1 nano-aggregates on human mature dendritic cells.
Priming by chemokines restricts lateral mobility of the adhesion receptor LFA-1 and restores adhesion to ICAM-1 nano-aggregates on human mature dendritic cells.
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DOI：
10.1371/journal.pone.0099589
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Garcia-Parajo MF
中科院分区：
文献类型：
--
作者：
Borgman KJ;van Zanten TS;Manzo C;Cabezón R;Cambi A;Benítez-Ribas D;Garcia-Parajo MF
LFA-1是白细胞特异性β2整合素，在调节不同免疫细胞的粘附和迁移中起主要作用。最近的数据表明，成熟树突状细胞（mDCs）上的LFA-1可能作为趋化因子诱导的锚在归巢的DCs通过传入神经系统进入淋巴结，通过瞬时转换其分子构象状态。然而，LFA-1的流动性在这一过程中的作用尚不清楚，尽管LFA-1介导的粘附调节的横向组织和动力学的重要性被广泛认可。使用单粒子跟踪方法，我们在这里表明，LFA-1表现出更高的流动性相比，单核细胞的静息mDC。类趋化因子CCL 21刺激mDC上的LFA-1高亲和力状态，导致迁移率显著降低和静止受体分数增加，与受体的再活化一致。在CCL 21存在下添加可溶性单体ICAM-1并不改变LFA-1的扩散曲线，而在CCL 21存在下添加可溶性ICAM-1纳米聚集体进一步降低了LFA-1的迁移率并易于与受体结合。总体而言，我们的研究结果强调了LFA-1跨膜横向流动性对整合素活化及其作为粘附受体功能的调节的重要性。重要的是，我们的数据表明，单独的趋化因子不足以触发整合素的高亲和力状态，这是基于亲和力是指单一受体与其配体在溶液中的粘附能力的严格定义。相反，我们的数据表明，由多配体结合诱导的受体的纳米簇，一旦LFA-1高亲和力状态被由内而外的信号瞬时触发，则需要维持稳定的细胞粘附。
LFA-1 is a leukocyte specific β2 integrin that plays a major role in regulating adhesion and migration of different immune cells. Recent data suggest that LFA-1 on mature dendritic cells (mDCs) may function as a chemokine-inducible anchor during homing of DCs through the afferent lymphatics into the lymph nodes, by transiently switching its molecular conformational state. However, the role of LFA-1 mobility in this process is not yet known, despite that the importance of lateral organization and dynamics for LFA-1-mediated adhesion regulation is broadly recognized. Using single particle tracking approaches we here show that LFA-1 exhibits higher mobility on resting mDCs compared to monocytes. Lymphoid chemokine CCL21 stimulation of the LFA-1 high affinity state on mDCs, led to a significant reduction of mobility and an increase on the fraction of stationary receptors, consistent with re-activation of the receptor. Addition of soluble monomeric ICAM-1 in the presence of CCL21 did not alter the diffusion profile of LFA-1 while soluble ICAM-1 nano-aggregates in the presence of CCL21 further reduced LFA-1 mobility and readily bound to the receptor. Overall, our results emphasize the importance of LFA-1 lateral mobility across the membrane on the regulation of integrin activation and its function as adhesion receptor. Importantly, our data show that chemokines alone are not sufficient to trigger the high affinity state of the integrin based on the strict definition that affinity refers to the adhesion capacity of a single receptor to its ligand in solution. Instead our data indicate that nanoclustering of the receptor, induced by multi-ligand binding, is required to maintain stable cell adhesion once LFA-1 high affinity state is transiently triggered by inside-out signals.
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