Mechanical forces regulate leukocyte migration in rapidly deforming tissues

机械力调节快速变形组织中的白细胞迁移

基本信息

批准号：
10463951
负责人：
Tanner Ford Robertson
金额：
$ 6.72万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10463951
关键词：
Actins Adhesives Affect Agonist Bathing Behavior Calcium Calcium Channel Cell physiology Cells Chemotactic Factors Chronic Collaborations Complex Confocal Microscopy Congenital Megacolon Data Defect Diagnosis Disease Family Filopodia Fluorescence Microscopy Genetic Gills Image Imaging Techniques Immobilization Immune Immunity Immunologics Impairment Infection Inflammation Inflammatory Inflammatory Bowel Diseases Intestinal Motility Intestines Ion Channel Leukocytes Ligands Light Measures Mechanics Microscopy Modeling Molecular Movement Muscle Contraction Muscle function Nifedipine Operative Surgical Procedures Outcome Pharmacology Physical Restraint Piezo 1 ion channel Positioning Attribute Process Reporter Rodent Rodent Model Role Sampling Scanning Signal Transduction Site Skin Smooth Muscle Stretching Structure System T-Lymphocyte Testing Thinness Tissues Visualization Zebrafish antagonist cell behavior cell motility enteric infection experience experimental study gastrointestinal infection genetic approach imaging approach inhibitor interstitial intravital imaging macrophage mechanical force mechanical signal migration mutant particle pathogen promoter tool

项目摘要

Project Summary Leukocytes must be able to infiltrate and migrate within essentially all tissues of the body in order to deal with infections and damage that occur throughout the host. Molecular signals like chemoattractants and adhesive ligands are critical for this process, but immune cells also sense and respond to mechanical cues. While most tissues of the body are relatively static, the intestines are mechanically dynamic due to the repetitive contractions of the smooth muscle layers, which apply compressive, stretch, and shear forces to the tissue. These forces are altered during intestinal infections and chronically dysregulated in inflammatory bowel disease, pointing towards a relationship between intestinal mechanics and inflammation. Leukocytes are exquisitely mechanosensitive, but it is presently unknown if they sense or respond to mechanical cues in the intestines directly. Investigating these forces in rodent models is challenging since the intestinal tissue needs to be physically immobilized for intravital imaging. Here, we propose to investigate the role intestinal forces on immune cell function by using the zebrafish system. Intestinal T lymphocytes can be directly visualized in this system without any surgical manipulation or tissue immobilization. With pharmacological and genetic tools that interfere with smooth muscle function, we can study intestinal T cell behavior in the presence and absence of mechanical deformation. In preliminary data, we have found that intestinal T cells migrate by a distinct strategy in the intestines relative to static tissues like the skin or gills, one characterized by thin, filopodia-like protrusions that undergo successive branching to propel the T cell forward. Blocking intestinal movement with smooth muscle inhibitors severely impairs T cell motility within the intestines, but not in static tissues like the skin. Collectively, these results suggest that mechanical cues dictate T cell migration strategies in the intestines. This proposal will investigate how T cells sense and respond to deformation in the intestines. Specifically, we will test the hypothesis that intestinal deformation activates the ion channel Piezo1 to promote filopodia-like migration. To our knowledge, this will be the first study to investigate how intestinal forces influence gut immunity and our findings could have broad implications for the diagnosis and treatment of inflammatory disorders of the gut.

项目概要白细胞必须能够在身体的几乎所有组织内渗透和迁移，以便处理整个宿主发生感染和损害。化学引诱剂和粘合剂等分子信号配体对于这一过程至关重要，但免疫细胞也能感知机械信号并做出反应。虽然大多数身体组织是相对静态的，而肠道由于重复的运动而具有机械动态性平滑肌层收缩，向组织施加压缩力、拉伸力和剪切力。这些力量在肠道感染期间发生改变，并在炎症性肠道中长期失调疾病，指出肠道力学与炎症之间的关系。白细胞是它们对机械力非常敏感，但目前尚不清楚它们是否能感知或响应机械信号直接进入肠道。在啮齿动物模型中研究这些力具有挑战性，因为肠道组织需要物理固定以进行活体成像。在这里，我们建议研究肠道力的作用利用斑马鱼系统研究免疫细胞功能。肠道 T 淋巴细胞可直接可视化该系统无需任何手术操作或组织固定。具有药理和遗传作用干扰平滑肌功能的工具，我们可以研究肠道 T 细胞的行为无机械变形。在初步数据中，我们发现肠道 T 细胞通过相对于皮肤或鳃等静态组织，肠道具有独特的策略，其特点是薄、丝状伪足状的突起经历连续的分支以推动 T 细胞前进。阻塞肠道平滑肌抑制剂的运动会严重损害肠道内 T 细胞的运动性，但静态情况下不会像皮肤一样的组织。总的来说，这些结果表明机械信号决定 T 细胞迁移策略在肠道里。该提案将研究 T 细胞如何感知肠道变形并做出反应。具体来说，我们将检验肠道变形激活离子通道 Piezo1 促进的假设丝状伪足样迁移。据我们所知，这将是第一项研究肠道力量如何影响肠道免疫力，我们的研究结果可能对诊断和治疗产生广泛影响肠道炎症性疾病。