A Bistable Mechanism Mediated by Integrins Controls Mechanotaxis of Leukocytes
A Bistable Mechanism Mediated by Integrins Controls Mechanotaxis of Leukocytes
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DOI：
10.1016/j.bpj.2019.12.013
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发表时间：
2020-02-04
影响因子：
3.4
通讯作者：
Valignat, Marie-Pierre
中科院分区：
文献类型：
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作者：
Hornung, Alexander;Sbarrato, Thomas;Valignat, Marie-Pierre
白细胞从血管募集到炎症区域是由生物化学和机械刺激引导的，其机制仅部分破译。在这里，我们研究了由原代人效应T淋巴细胞在涂有整合素淋巴细胞功能相关抗原1（LFA-1）（α（L）β（2））和极晚期抗原4（VLA-4）（α（4）β（1））配体的基质上爬行的流动的指导。我们发现，细胞分离在两个群体的相反方向的联合粘附，并显示方向的决定依赖于LFA-1介导的上游和VLA-4介导的下游表型之间的相互作用机制。在分子水平上，双稳态是由两种整联蛋白亲和力的差异前后极化以及LFA-1对VLA-4的抑制性串扰引起的。在细胞水平，方向是由被动的，流动介导的方向的非粘附细胞部分，后尾足的上游迁移，和前片足的下游迁移。这个逻辑事件链提供了一个全面的指导机制，从刺激到细胞定向。
Recruitment of leukocytes from blood vessels to inflamed zones is guided by biochemical and mechanical stimuli, with the mechanisms only partially deciphered. Here, we studied the guidance by the flow of primary human effector T lymphocytes crawling on substrates coated with ligands of integrins lymphocyte function-associated antigen 1 (LFA-1) (alpha(L)beta(2)) and very late antigen 4 (VLA-4) (alpha(4)beta(1)). We reveal that cells segregate in two populations of opposite orientation for combined adhesion and show that decisions of orientation rely on a bistable mechanism between LFA-1-mediated upstream and VLA-4-mediated downstream phenotypes. At the molecular level, bistability results from a differential front-rear polarization of both integrin affinities, combined with an inhibiting cross talk of LFA-1 toward VLA-4. At the cellular level, direction is determined by the passive, flow-mediated orientation of the nonadherent cell parts, the rear uropod for upstream migration, and the front lamellipod for downstream migration. This chain of logical events provides a comprehensive mechanism of guiding, from stimuli to cell orientation.