Integrative genomic and epigenomic profiling reveals cell-type specific signaling networks in activated lung mononuclear phagocytes [scRNA-seq]

The lung is inhabited by resident alveolar and interstitial macrophages as well as monocytic cells that survey the lung. Each cell type plays distinct functional roles under homeostatic and inflammatory conditions, but mechanisms establishing their molecular identities and functional potential remain poorly understood. Here, systematic evaluation of transcriptomes and open chromatin of alveolar macrophages (AMs), interstitial macrophages (IMs) and lung monocytes from two mouse strains enabled inference of common and cell-specific transcriptional regulators. We provide evidence that these factors drive selection of regulatory landscapes that specify distinct phenotypes of AMs and IMs and entrain qualitatively different responses to TLR4 signaling in vivo. These studies reveal a striking divergence in a fundamental innate immune response pathway in AMs and establish a framework for further understanding macrophage diversity in the lung. Overall design: Single-cell RNA-seq of FACS we isolated lung myeloid cells from 2 week old male DBA/2J mouse.