Petrie Aronin Caren E, Zhao Yun M, Yoon Justine S, Morgan Nicole Y, Prüstel Thorsten, Germain Ronald N, Meier-Schellersheim Martin
Laboratory of Systems Biology (LSB), Lymphocyte Biology Section (LBS), National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.
Biomedical Engineering and Physical Sciences Resource (BEPS), Microfabrication and Microfluidics Unit (MMU), National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA.
Immunity. 2017 Nov 21;47(5):862-874.e3. doi: 10.1016/j.immuni.2017.10.020.
Chemoattractant-mediated recruitment of hematopoietic cells to sites of pathogen growth or tissue damage is critical to host defense and organ homeostasis. Chemotaxis is typically considered to rely on spatial sensing, with cells following concentration gradients as long as these are present. Utilizing a microfluidic approach, we found that stable gradients of intermediate chemokines (CCL19 and CXCL12) failed to promote persistent directional migration of dendritic cells or neutrophils. Instead, rising chemokine concentrations were needed, implying that temporal sensing mechanisms controlled prolonged responses to these ligands. This behavior was found to depend on G-coupled receptor kinase-mediated negative regulation of receptor signaling and contrasted with responses to an end agonist chemoattractant (C5a), for which a stable gradient led to persistent migration. These findings identify temporal sensing as a key requirement for long-range myeloid cell migration to intermediate chemokines and provide insights into the mechanisms controlling immune cell motility in complex tissue environments.
趋化因子介导造血细胞向病原体生长或组织损伤部位募集，这对宿主防御和器官稳态至关重要。趋化作用通常被认为依赖于空间感知，只要存在浓度梯度，细胞就会沿着浓度梯度移动。利用微流控方法，我们发现中间趋化因子（CCL19和CXCL12）的稳定梯度未能促进树突状细胞或中性粒细胞的持续定向迁移。相反，需要趋化因子浓度上升，这意味着时间感知机制控制着对这些配体的延长反应。发现这种行为依赖于G偶联受体激酶介导的受体信号负调控，并且与对终末激动剂趋化因子（C5a）的反应形成对比，对于C5a，稳定梯度会导致持续迁移。这些发现确定时间感知是髓样细胞向中间趋化因子进行长距离迁移的关键要求，并为控制复杂组织环境中免疫细胞运动的机制提供了见解。
