科研动态 | 王畯霖、叶德全提出配体浓度依赖性调控吞噬细胞功能新机制

定向迁移 (directional migration) 是细胞的基本功能之一，在生长发育、组织修复、天然免疫、肿瘤转移等过程中起到重要作用。细胞迁移受趋化因子诱导，其剂量曲线呈正态分布，与其它细胞功能的“S”形剂量曲线有明显不同（图A）。为何细胞定向迁移受高浓度配体抑制，是学术界多年来未能圆满解答的一个问题。

Directional migration is a basic cell function critical to growth, tissue repair, innate immunity and tumor migration. Cell migration is induced by chemoattractants, with a bell-shaped dose response curve that differs from the typical “S” shaped dose curve of other cellular functions (Panel A). How cell migration is inhibited by high dose agonist is an unresolved question in the research field.

本期《美国国家科学院院刊》(Proceedings of the National Academy of Sciences of the United States of America) 刊出医学院王畯霖博士和叶德全教授署名的学术论文*，提出配体剂量依赖性调控细胞迁移的新理论并展示支持这一理论的实验结果。他们以源于细菌的甲酰肽趋化因子为配体，观察到不同浓度的配体可刺激细胞内钙离子产生不同的变化，其中低剂量配体引起细胞内钙离子浓度梯度的形成为细胞迁移所必需（图B）。受高浓度配体刺激后，细胞表面钙离子通道开放造成胞内钙离子浓度迅速上升，梯度不复存在，细胞迁移停止（图C）。这项研究同时发现了与细胞迁移及胞内钙离子动态变化相关的受体构象，并以嗜中性粒细胞为例，阐述了配体剂量依赖性调控在病原菌清除过程中如何协调细胞迁移、脱颗粒及超氧产生等天然免疫功能。

In the current issue of PNAS (July 25, 2022), a research article by Junlin Wang and Richard D. Ye of School of Medicine proposed a new hypothesis of agonist concentration-dependent regulation of cell migration and presented supporting data for the hypothesis. Using a bacterial formyl peptide with chemotactic activity, they observed changes in intracellular calcium ion (Ca2+) induced by different concentration of the peptide agonist. An intracellular Ca2+ concentration gradient, required for directional migration of the cell, was present when the cells were stimulated with low concentrations of the agonist (Panel B). However, exposure to high concentrations of the same agonist caused opening of cell surface calcium channel and sudden rise of intracellular Ca2+ concentration with concurrent loss of the Ca2+ gradient, thereby abrogating cell migration (Panel C). The present study also identified receptor conformations associated with cell migration and the formation of intracellular Ca2+ concentration gradient, and used neutrophils as an example to illustrate the orchestrated actions of cell migration, degranulation and superoxide production in the elimination of invading bacteria.

本文第一作者王畯霖博士目前在科比尔卡研究院从事博士后研究；通讯作者叶德全教授是科比尔卡研究院成员，校长讲座教授、医学院副院长。这项研究得到科技部重大专项、深圳湾实验室开放课题、深圳市基础研究项目、中国博士后第70批基金的支持。课题组成员常艺馨、徐聪聪等参与并协助血细胞的分离。

The first author of the PNAS article, Dr. Junlin Wang, is currently a postdoctoral fellow at the Kobilka Institute of Innovative Drug Discovery. The corresponding author, Richard D. Ye, is a member of the Kobilka Institute, Presidential Chair Professor and Associate Dean of School of Medicine. This study was supported by a National Key R&D Program of China, Shenzhen Bay Laboratory Open Project, Shenzhen Natural Science Foundation Project, and the 70th batch of General Projects from China Postdoctoral Science Foundation. Members of the Ye Lab including Ms. Chang Yixin and Ms. Xu Congcong provided help in blood cell preparation.

* Wang J, Ye RD. Agonist concentration-dependent changes in FPR1 conformation lead to biased signaling for selective activation of phagocyte functions. Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2201249119. doi: 10.1073/pnas.2201249119. Epub 2022 Jul 25.

文案、图片：叶德全教授课题组

编辑出品 ：医学院传讯公关办公室