Bach2 keeps homeostasis in lung by regulating inflammatory response and maintaining function of alveolar macrophage [array]. Mus musculus

Tissue resident macrophages show their specific function to maintain homeostasis in our body. Dysfunction of alveolar macrophages (AMs), which regulate the proper amount of surfactant protein, leads to the development of pulmonary alveolar proteinosis (PAP). Here we found that inflammation ruins the function of AMs and is one of the causes of secondary PAP. Inflammation leads to the loss of specific gene expression pattern of AMs and furthermore, it leads to gain the specific gene expression pattern of other tissue resident macrophages and DC lineage. We also found the critical roles for Bach2 expressed in AMs and T cells, whose expression is induced by IFNg released from T cells. Bach2 bounds to super-enhancer regions of the inflammatory genes of the myeloid lineage and represses excess inflammation in lungs. Our results suggest that Bach2 function among several cell lineages to modify the inflammation, maintaining homeostasis in lungs. Overall design: Gene expression in alveolar macrophage from WT, Bach1 KO, Bach2 KO and Bach1/Bach2 DKO mouse was measured. 3 independent mice were used for each genotype.

组织驻留巨噬细胞（tissue resident macrophages）发挥特定功能以维持机体稳态。调控表面活性蛋白水平的肺泡巨噬细胞（alveolar macrophages, AMs）功能异常，可引发肺泡蛋白沉积症（pulmonary alveolar proteinosis, PAP）。本研究发现，炎症会破坏肺泡巨噬细胞的功能，是继发性肺泡蛋白沉积症的诱因之一。炎症可导致肺泡巨噬细胞丧失其特异性基因表达谱，转而获得其他组织驻留巨噬细胞及树突状细胞（dendritic cell, DC）谱系的特异性基因表达谱。我们还鉴定出在肺泡巨噬细胞与T细胞中表达的Bach2的关键作用：Bach2的表达由T细胞释放的干扰素γ（interferon gamma, IFNg）诱导。Bach2可结合髓系谱系炎症基因的超级增强子区域，抑制肺部过度炎症反应。本研究结果表明，Bach2可通过作用于多种细胞谱系以调控炎症反应，维持肺部稳态。实验整体设计：对野生型（wild type, WT）、Bach1基因敲除（Bach1 KO）、Bach2基因敲除（Bach2 KO）以及Bach1与Bach2双基因敲除（Bach1/Bach2 DKO）小鼠的肺泡巨噬细胞进行基因表达量检测，每种基因型使用3只独立小鼠作为实验样本。