Heterogeneous immune responses of the alveolar macrophage population during pulmonary fungal infections

项目摘要/摘要 肺泡巨噬细胞(AM)是驻留在肺内的巨噬细胞。它们是最早 遇到吸入的真菌病原体。目前，AM在真菌感染中的作用仍然难以捉摸；一些文章 据报道，AM具有保护性，但其他人表明它们是有害的。研究AM的挑战在于 活体AM的鉴定和评价需要多色流式细胞术、报告和 命运映射(FM)小鼠系统，以及单细胞水平的基因表达分析。通过使用这些 技术，我们将阐明AM在肺部真菌感染中的生物学功能。 我们最近证明AM是对真菌感染作出反应的真正的免疫哨兵。 还能引起异种免疫反应。特别是，真菌感染会产生有利于和反对的 炎症性AM亚群与功能不同的AM亚群共存 肺部感染。这种AM种群内的异质性不能通过肺内滴注Toll-1来诱导。 与最近的配体一样，表明真菌感染可能具有特异性，可能是通过C-型凝集素受体 发信号。 这项研究的中心假设是：AM在体内发育为促炎和抗炎AM 活体分别在转录水平和表观遗传水平进行调控。AM亚群的产生 具有二分功能被认为是最大限度地清除真菌并将附带损害降至最低 阿龙。这项拟议研究的目的是确定不同功能AM的生物学意义 并阐明异质性AM的详细分子机制 在体内真菌感染期间，亚群被产生、维持和丢失。

PROJECT SUMMARY/ABSTRACT Alveolar macrophages (AMs) are lung-resident macrophages. They are one of the cell types that first encounter inhaled fungal pathogens. Currently, the role of AMs in fungal infections is still elusive; some articles reported AMs to be protective, but others showed them detrimental. The challenge to study AMs is that identification and evaluation of AMs in vivo require technologies such as; multi-color flow cytometry, reporter and fate-mapping (FM) mouse systems, and single cell-level of gene expression analyses. By using these technologies, we will elucidate the biological functions of AMs during pulmonary fungal infections. We recently demonstrated that AMs are the bona fide immune sentinels that respond to fungal infections and also elicit heterogeneous immune responses. In particular, fungal infections generate pro- and anti- inflammatory AM subpopulations simultaneously, and AM subpopulations with distinct functions co-exist in the infected lung. Such heterogeneity within the AM population cannot be elicited by pulmonary instillation of Toll- like recent ligands, suggesting possible specificity in fungal infections, likely through C-tyle lectin receptor signaling. The central hypothesis of this proposed study is: AMs develop into pro- and anti-inflammatory AMs in vivo at the level of transcriptional and epigenetic regulations, respectively. The generation of AM subpopulations with dichotomous functions is considered to maximize fungal clearance and minimize collateral damage in the lung. The objective of this proposed study is to identify the biological implication of functionally distinct AM subpopulations and to elucidate the detailed molecular mechanism by which the heterogeneous AM subpopulations are generated, maintained, and lost during fungal infections in vivo.