Tissue recruitment of type 2 effector cells

肺的过敏性炎症和特应性皮炎是2型免疫驱动疾病的两个突出实例，其中免疫系统的几种不同的IL-4/IL-13表达效应细胞分别进入肺或皮肤，并引起病理学。已知IL-4/IL-13诱导的转录因子STAT 6在嗜酸性粒细胞和其他效应细胞的募集中起关键作用，但基质或造血细胞中哪些STAT 6调节的基因对该过程至关重要的定义不清楚。因此，在本研究项目中，我们将研究STAT 6依赖性机制调节2型免疫应答期间表达IL-4/IL-13的效应细胞（包括嗜酸性粒细胞）的发育和组织募集。我们将通过鼻内应用活分生孢子建立烟曲霉诱导的过敏性肺部炎症模型。对于皮肤中的2型免疫应答，我们将使用特应性皮炎的IgE和嗜碱性粒细胞依赖性模型和TSLP依赖性模型。我们将分析STAT 6调节基因在各种造血细胞类型，内皮细胞或上皮细胞和角质形成细胞外渗效应细胞的要求。我们将进一步研究编码整合素和嗜酸性粒细胞或嗜碱性粒细胞中其他粘附蛋白的单个基因的缺失如何影响它们的组织迁移。最后，我们将使用我们新产生的AAN命运映射和删除小鼠研究交替激活的巨噬细胞（AAM）在肺部和皮肤炎症和伤口愈合中的作用。

Allergic inflammation of the lung and atopic dermatitis are two prominent examples of type 2 immunity-driven diseases where several different IL-4/IL-13-expressing effector cells of the immune system enter the lung or skin, respectively, and cause pathology. The IL-4/IL-13-induced transcription factor STAT6 is known to play a critical role for recruitment of eosinophils and other effector cells but it is poorly defined, which STAT6-regulated genes in stromal or hematopoietic cells are critical for this process. In this research project we will therefore investigate the STAT6-dependent mechanisms regulating development and tissue recruitment of IL-4/IL-13-expressing effector cells including eosinophils during type 2 immune responses. We will work with a model of Aspergillus fumigatus-induced allergic lung inflammation by intranasal application of live conidia. For type 2 immune responses in the skin we will use an IgE- and basophil-dependent model and a TSLP-dependent model of atopic dermatitis. We will analyze the requirement of STAT6-regulated genes in various hematopoietic cell types, endothelial cells or epithelial cells and keratinocytes for extravasation of effector cells. We will further study how deletion of individual genes encoding integrins and other adhesion proteins in eosinophils or basophils affects their tissue migration. Finally, we will study the role of alternatively activated macrophages (AAMs) in inflammation and wound healing in lung and skin using our newly generated AAN fate mapping and delete mice.