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

• 批准号: 10658854
• 负责人: Tanner Ford Robertson
• 金额: $ 6.95万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/10658854
• 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; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Motility; Intestines; Ion Channel; Leukocytes; Ligands; Light; Macrophage; Measures; Mechanics; Microscopy; Modeling; Molecular; Movement; Muscle Contraction; Muscle function; Nifedipine; Operative Surgical Procedures; Outcome; 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; mechanical force; mechanical signal; migration; mutant; particle; pathogen; pharmacologic; promoter; tool

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.

项目摘要 白细胞必须能够在身体的所有组织中浸润和迁移 整个主机中发生的感染和损害。分子信号等分子信号和胶粘剂 配体对于此过程至关重要，但是免疫细胞也感知并响应机械提示。虽然大多数 人体的组织相对静态，由于重复性而在机械上是动态的 平滑肌层的收缩，它们在组织上施加压缩，拉伸和剪切力。 这些力在肠道感染过程中改变，并且在炎症性肠中慢性失调 疾病，指向肠道力学与炎症之间的关系。白细胞是 精确的机械敏感，但目前尚不清楚它们是否感知或响应机械线索 直接肠。在啮齿动物模型中调查这些力是具有挑战性的，因为肠组织需要 在物理上固定以进行浸润成像。在这里，我们建议研究肠道的作用 通过使用斑马鱼系统在免疫细胞功能上。肠道T淋巴细胞可以直接在 该系统没有任何手术操纵或固定组织。用药理学和遗传 干扰平滑肌功能的工具，我们可以在存在下研究肠道T细胞行为 没有机械变形。在初步数据中，我们发现肠道T细胞通过A迁移 肠道中相对于静态组织（如皮肤或ill）的二st剂中的独特策略，一种以薄为特征 经过连续的分支以推动T细胞向前的类似丝状虫样突起。阻塞肠道 使用平滑肌抑制剂运动严重损害肠内的T细胞运动，但不会静态 像皮肤这样的组织。总的来说，这些结果表明机械提示决定了T细胞迁移策略 在肠道中。该建议将研究T细胞如何感知并响应肠道中的变形。 具体而言，我们将检验以下假设：肠变形激活离子通道压电以促进 类似丝状的迁移。据我们所知，这将是首次研究肠子的研究 影响肠道免疫力，我们的发现可能对诊断和治疗具有广泛的影响 肠道疾病。