Biology subjects

Bain, C. C.

Publications and source records attributed to Bain, C. C..

4 recordsLinked to original sources

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↗

bioRxiv2020

Recruited macrophages that colonise the post-inflammatory peritoneal niche convert into functionally divergent resident cells

Inflammation generally leads to substantial recruitment of monocyte-derived macrophages. What regulates the fate of these cells and to what extent they can assume the identity and function of resident macrophages remains unclear. We compared the normal fate of inflammation-elicited macrophages in the peritoneal cavity with their potential under non-inflamed conditions and in the absence of established resident macrophages. Following mild inflammation, elicited macrophages persisted for at least 5 months but failed to fully assume a GATA6hi resident identity due to the presence of enduring resident cells. In contrast, severe inflammation resulted in ablation of resident macrophages and a protracted phase wherein the cavity was incapable of sustaining a resident phenotype, yet ultimately elicited cells acquired a mature GATA6hi identity. Elicited macrophages also exhibited divergent features resulting from inflammation-driven alterations to the peritoneal cavity micro-environment and environment-independent features related to origin and time-of-residency. Critically, one environment-dependent feature of inflammation-elicited macrophages irrespective of severity of inflammation was a failure to produce the chemokine CXCL13, which correlated with a progressive loss in accumulation of peritoneal B1 cells post-inflammation. Hence, rather than being predetermined, the fate of inflammation-elicited peritoneal macrophages appears largely regulated by environment, changes in which result in long-term alteration in function of the peritoneal macrophage compartment post-inflammation.

immunology↗

bioRxiv2019

Origin and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages.

Macrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the aetiology of pathologies including peritonitis, endometriosis and metastatic cancer thus understanding the factors that govern their behaviour is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and age on murine peritoneal macrophage differentiation, turnover and function. We demonstrate that the sexually dimorphic replenishment of peritoneal macrophages from the bone marrow, which is high in males and very low in females, is driven by changes in the local microenvironment that arise upon sexual maturation. Population and single cell RNAseq revealed striking dimorphisms in gene expression between male and female peritoneal macrophages that was in part explained by differences in composition of these populations. By estimating the time of residency of different subsets within the cavity and assessing development of dimorphisms with age and in monocytopenic Ccr2-/- mice, we demonstrate that key sex-dependent features of peritoneal macrophages are a function of the differential rate of replenishment from the bone marrow while others are reliant on local microenvironment signals. Importantly, we demonstrate that the dimorphic turnover of peritoneal macrophages contributes to differences in the ability to protect against pneumococcal peritonitis between the sexes. These data highlight the importance of considering both sex and age in susceptibility to inflammatory and infectious disease.

immunology↗