Mechanical forces regulate leukocyte migration in rapidly deforming tissues

项目摘要 白细胞必须能够在身体的基本上所有组织内浸润和迁移，以便处理白细胞。 感染和损害发生在整个主机。分子信号，如化学引诱物和粘合剂 配体对于这一过程至关重要，但免疫细胞也能感知并响应机械信号。虽然大多数 身体的组织是相对静止的，肠道由于重复的运动而机械地是动态的。 平滑肌层的收缩，其向组织施加压缩、拉伸和剪切力。 这些力量在肠道感染期间发生改变，在炎症性肠病中长期失调 疾病，指向肠道力学和炎症之间的关系。白细胞 它们对机械敏感，但目前尚不清楚它们是否能感觉到或对机械线索作出反应。 肠直接。在啮齿动物模型中研究这些力量是具有挑战性的，因为肠道组织需要 为了活体成像而被物理固定。在这里，我们建议调查肠道力量的作用， 对免疫细胞功能的影响。肠道T淋巴细胞可以直接在 该系统无需任何外科手术操作或组织固定。通过药理学和遗传学 干扰平滑肌功能的工具，我们可以研究肠道T细胞的行为， 没有机械变形。在初步的数据中，我们发现肠道T细胞通过一种 相对于皮肤或鳃等静态组织，肠道中的独特策略，一个特征是薄， 丝状伪足样突起，经历连续的分支以推动T细胞前进。肠梗阻 运动与平滑肌抑制剂严重损害T细胞的运动在肠道内，但不是在静态 组织如皮肤。总的来说，这些结果表明，机械线索支配T细胞迁移策略 在肠子里该提案将研究T细胞如何感知和响应肠道变形。 具体地说，我们将测试肠道变形激活离子通道Piezo1以促进 丝状伪足样迁移。据我们所知，这将是第一个研究肠道力量是如何 影响肠道免疫，我们的发现可能对诊断和治疗 肠道的炎症性疾病。

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.