The role of immune cell migration in gut-liver crosstalk during homeostasis, tolerance, and inflammation

免疫细胞的定向迁移对免疫反应的调节至关重要，并受到趋化因子和粘附分子的特异性和相互作用的保护。选择性抑制免疫细胞迁移作为一种治疗手段，已进入临床应用阶段。靶向抑制的先决条件是确定促进疾病的细胞类型、它们的迁移行为、负责的归巢受体以及这些受体的功能。近年来，我们通过生成和分析基因靶向小鼠，剖析了粘附分子β 7整合素和MAdCAM-1的功能。这表明，β 7整合素和MAdCAM-1对于免疫细胞迁移到胃肠道至关重要，并通过募集必要的细胞来促进免疫原性和耐受性免疫反应。现在我们希望将研究扩展到肝脏。肠道吸收的所有营养物质都要经过肝脏，肠道中异常的免疫反应可诱发肝脏病变，肝脏中可诱导口服耐受，这是防止对无害营养抗原免疫反应的关键机制。因此，我们计划描述亲肠黏附分子对体内平衡和炎症性肠-肝串扰的贡献。利用黏附分子缺陷小鼠，我们首先需要确定黏附分子如何促进肝脏特异性迁移和免疫细胞在稳态中的定位。此外，免疫细胞迁移在炎症条件下的作用将在肝炎的实验模型中进行评估。通过结合实验性IBD和肝炎模型，我们旨在确定IBD可能支持肝脏炎症的迁移依赖性后果。我们还想确定黏附分子依赖性细胞迁移在浆细胞样树突状细胞（pDC）介导的口服耐受诱导中的作用。pccs在肝脏中建立的口服耐受中起关键作用，但目前尚不清楚pccs如何迁移到肝脏，以及是否有pccs从肠道运输到肝脏。我们计划在免疫和耐受性的背景下通过一系列pDC转移实验在体内解决这一问题。调节免疫细胞迁移以控制人类慢性炎症现已被认为是一项重要的治疗进展。因此，通过提高我们对调节细胞迁移的生物制剂的理解，并帮助塑造它们未来的用途，我们的研究将具有很大的价值。

Directed migration of immune cells is critical for the regulation of immune responses and is secured by the specificity and interactions of chemokines and adhesion molecules. As a therapeutic approach, selective inhibition of immune cell migration has already reached the stage of clinical application. A prerequisite for targeted inhibition is the identification of the disease promoting cell types, their migration behavior, the homing receptors responsible, and the functions of those receptors. In recent years we have dissected the functions of the adhesion molecules beta7 integrin and MAdCAM-1 by generating and analyzing gene-targeted mice. This has demonstrated that beta7 integrin and MAdCAM-1 are essential for the migration of immune cells into the gastrointestinal tract and contribute to immunogenic and tolerogenic immune responses by recruiting the necessary cells. We now wish to extend our studies to the liver. All nutrients absorbed by the intestine pass through the liver, aberrant immune responses in the gut can induce liver pathology, and oral tolerance, a critical mechanism preventing immune reaction towards harmless nutritive antigens, can be induced in the liver. We therefore plan to delineate the contribution of gut-tropic adhesion molecules to homeostatic and inflammatory gut-liver crosstalk. Utilizing adhesion molecule-deficient mice, we will first need to determine how adhesion molecules contribute to liver-specific migration and localization of immune cells in homeostasis. Moreover, the role of immune cell migration under inflammatory conditions will be evaluated in experimental models of hepatitis. By combining experimental IBD and hepatitis models, we then aim to identify migration-dependent consequences of IBD that might support liver inflammation. We also want to define the role of adhesion molecule-dependent cell migration for the plasmacytoid dendritic cell (pDC) mediated induction of oral tolerance. pDCs are critically involved in oral tolerance established in the liver but it is not yet known how pDCs migrate to the liver and whether there is pDC trafficking from the gut to the liver. We plan to address this issue in vivo by a series of pDC transfer experiments in the context of immunization and tolerization.Modulation of immune cell migration for control of chronic inflammation in humans is now recognized as an important therapeutic advance. Thus, by improving our understanding of biologicals that modulate cell migration and helping to shape their future use, our studies will be of great value.