Jones, G.-R. | bioRxiv Science

bioRxiv2021

The transcription factor EGR2 is indispensable for tissue-specific imprinting of alveolar macrophages in health and tissue repair

Alveolar macrophages are the most abundant macrophages in the healthy lung where they play key roles in homeostasis and immune surveillance against air-borne pathogens. Tissue-specific differentiation and survival of alveolar macrophages relies on niche-derived factors, such as colony stimulating factor 2 (CSF-2) and transforming growth factor beta (TGF-{beta}). However, the nature of the downstream molecular pathways that regulate the identity and function of alveolar macrophages and their response to injury remains poorly understood. Here, we identify that the transcriptional factor EGR2 is an evolutionarily conserved feature of lung alveolar macrophages and show that cell-intrinsic EGR2 is indispensable for the tissue-specific identity of alveolar macrophages. Mechanistically, we show that EGR2 is driven by TGF-{beta} and CSF-2 in a PPAR-{gamma}-dependent manner to control alveolar macrophage differentiation. Functionally, EGR2 was dispensable for lipid handling, but crucial for the effective elimination of the respiratory pathogen Streptococcus pneumoniae. Finally, we show that EGR2 is required for repopulation of the alveolar niche following sterile, bleomycin-induced lung injury and demonstrate that EGR2-dependent, monocyte-derived alveolar macrophages are vital for effective tissue repair following injury. Collectively, we demonstrate that EGR2 is an indispensable component of the transcriptional network controlling the identity and function of alveolar macrophages in health and disease. One Sentence SummaryEGR2 controls alveolar macrophage function in health and disease

immunology↗

bioRxiv2021

Single-cell characterisation of mononuclear phagocytes in the human intestinal mucosa

Mononuclear phagocytes (MNP), including macrophages and classical dendritic cells (cDC), are highly heterogeneous cells with distinct functions. Understanding MNP complexity in the intestinal lamina propria (LP), particularly in humans, has proved difficult due to the expression of overlapping phenotypic markers and the inability to isolate these cells without contamination from gut-associated lymphoid tissues (GALT). Here, we exploited our novel method for isolation of human GALT-free LP to carry out single-cell (sc)RNA-seq, CITE-seq and flow cytometry analysis of human ileal and colonic LP MNPs. As well as classical monocytes, non-classical monocytes, mature macrophage subsets, cDC1s, and cDC2s, we identified a CD1c+ cDC subset with features of both cDC2 and monocytes, which were transcriptionally similar to the recently described cDC3. While similar MNP subsets were present in both ileal and colonic LP, the proportions and transcriptional profiles of these populations differed between these sites and in diseased states, indicating local specialization and environmental imprinting. Using computational trajectory tools, we identified putative early committed pre-cDC subsets and developmental intermediates of mature cDC1, cDC2 and cDC3, as well as monocyte-to-macrophage trajectories. Collectively, our results provide novel insights into the heterogeneity and development of intestinal LP MNP and an important framework for studying the role of these populations in intestinal homeostasis and disease. One sentence summaryFenton and Wulff et al. use single-cell methods to explore the complexity of the mononuclear phagocyte compartment of the human intestinal lamina propria, identifying distinct dendritic cell and macrophage subsets, site-specific transcriptional signatures, and lineage-specific precursors.

immunology↗