Biology subjects

Jones, G.-R.

Publications and source records attributed to Jones, G.-R..

8 recordsLinked to original sources

bioRxiv2026

Diverse lung challenges elicit a conserved monocyte-to-macrophage differentiation blueprint

Alveolar macrophages (AM) form a first line of defence to lung insults. These insults often lead to replacement of foetal-derived tissue-resident AMs (fAMs) by monocyte-derived AMs (mono-AMs) with different functionality, which impacts lung immunity long-term. However, whether these alterations are conserved or insult-specific is not well understood. Here, we show that respiratory syncytial virus (RSV) infection remodels the AM compartment long-term. We perform comparative analyses of fAMs and mono-AMs after RSV infection, influenza (IAV) infection and clodronate liposome administration to derive rules governing the functional and transcriptional changes in AM across insults. We identify a crucial tissue integration checkpoint of CD11b+ mono-AMs which involves acquisition of proliferative capacity and requires EGR2-mediated transcriptional rewiring. Mono-AMs elicited by RSV, influenza or clodronate liposomes have a hard-wired ontogeny-dependent stereotypical profile of transcription, metabolism and enhanced immunoreactivity despite a substantially different inflammatory environment during differentiation; accordingly, mono-AMs, whether elicited by infection or sterile depletion, protect from subsequent S. pneumoniae infection. By contrast, fAMs are more susceptible to subtle, context-dependent transcriptional alterations. Our findings highlight that long-term changes in the AM compartment show origin-dependent phenotypic divergence and that mono-AM integration follows a hard-wired trajectory fine-tuned by environmental factors.

immunology↗

bioRxiv2025

Tissue resident colonic macrophages persist through acute inflammation and adapt to aid tissue repair

Macrophages are crucial for the maintenance of intestinal homeostasis, are considered key proinflammatory effector cells during intestinal inflammation and are implicated in tissue repair following injury or inflammation. Whether these roles are attributed to distinct subsets of macrophages or if macrophages retain a degree of plasticity in the intestine remains poorly understood. Here, through a combination of single cell RNA sequencing, lineage-tracing and immunofluorescence imaging, we define three major subpopulations of murine, colonic macrophages on the basis of CD11c and CD163 expression. These macrophages occupy discrete anatomical niches and display distinct replenishment kinetics. They all accumulate during acute colitis and Cx3cr1-based fate mapping shows that they persist through to inflammation resolution. Moreover, marked transcriptional differences exist between the macrophages present in health and their counterparts in the post-inflammation environment, demonstrating that inflammation leads to transcriptional rewiring of the resident macrophages in a subset-specific manner. Intriguingly, there were minimal transcriptional changes between long-lived macrophages and their recently differentiated counterparts, indicating the environment exerted a greater influence than ontogeny or the time of residency on their functional states in resolution.

immunology↗

bioRxiv2025

Loss of HMGCS2-mediated intestinal stem cell ketogenesis is a metabolic barrier to mucosal healing in Ulcerative colitis

Human colonic epithelial cells express high levels of 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the crucial mitochondrial enzyme responsible for the production ketone bodies, predominantly beta-hydroxybutyrate ({beta}HB). Ketogenesis is an important metabolic pathway responsible for energy production in states of fasting and in the intestine ketone bodies are also important in regulating intestinal stem cell (ISC) homeostasis and regeneration. Using combined single-cell and spatial transcriptomics, organoids and prospective longitudinal mucosal analysis, we demonstrated a profound loss of ISC HMGCS2-mediated ketogenesis with consequential detrimental effect on Ulcerative colitis (UC), a chronic inflammatory bowel disease that affects [~]4 million individuals worldwide. We show that {beta}HB restores UC ISC metabolic function, reduces cellular stress with further evidence of epigenetic programming key for restoration of ISC function. Furthermore, low colonic HMGCS2 expression is associated with treatment failure of multiple biological immune therapies in UC. Our findings reveal the crucial role for HMGCS2 and loss of ketogenesis as the tipping point for pathogenic epithelial dysfunction and importantly, a promising metabolic therapeutic target for UC.

cell biology↗

bioRxiv2025

A Human Single-cell Atlas Identifies OLR1+ Scar-associated Macrophages as a Therapeutic Target for Chronic Liver Disease

Chronic liver disease (CLD) is a major global healthcare problem. Irrespective of cause, chronic damage to the liver results in fibrosis, which is associated with adverse clinical outcomes. Immune cells, in particular monocyte-derived macrophages (MDMs), are key regulators of fibrosis and represent an attractive therapeutic target for CLD. However, it has remained unclear which specific subpopulation of MDMs drives pro-inflammatory and pro-fibrotic functions in human CLD and how they might be selectively modulated. Here, we generate an annotated human liver single cell atlas from 42 healthy and 35 CLD patients, identifying 125 transcriptionally distinct cellular states. Leveraging large patient and cell numbers, our atlas resolves rare liver cell states and distinguishes two types of disease-expanded scar-associated macrophages (SAMac), including a specific subpopulation with a pro-inflammatory pro-fibrotic phenotype. The scavenger receptor OLR1 was enriched in pro-inflammatory SAMacs and high hepatic OLR1 expression was associated with increased mortality in CLD patients. A corresponding monocyte-derived OLR1+ SAMac subpopulation expanded in a mouse model of CLD and exhibited a pro-inflammatory phenotype based on single-cell RNA-seq, single-cell ATAC-seq, and flow cytometry analyses. Primary human OLR1+ MDMs promoted fibrogenic signalling in multilineage liver spheroid cultures, whilst specific targeting of OLR1 reduced IL-1{beta} production by human macrophages and attenuated myofibroblast activation. Overall, our annotated human liver single-cell atlas provides a valuable reference to study disease-associated cell states in CLD. We utilise this resource to identify a distinct pro-inflammatory subpopulation of SAMacs and highlight OLR1 as a potential therapeutic target to specifically modulate SAMac function and attenuate liver fibrosis.

immunology↗

bioRxiv2024

Inflammation-associated monocytes express ACOD1 to curtail inflammatory behaviour in IBD and experimental colitis

Monocytes are essential for replenishing homeostatic macrophages in the intestine. However, they also accumulate in significant numbers when intestinal homeostasis is disrupted in diseases, such as inflammatory bowel disease (IBD). The molecular pathways governing monocyte behaviour across these different contexts remain poorly understood. Here, we profile the monocyte / macrophage compartment in human IBD using single-cell RNA sequencing and identify a discrete population of monocytes that accumulate in IBD, which we term inflammation associated monocytes (IAMs). These can be identified by the expression of CD319, CD274 and CCRL2, and demonstrate increased expression of IBD susceptibility genes. By performing cross-species analysis, we show an analogous population of IAMs accumulate during chemically induced colitis in mice. Using transgenic fate mapping approaches, we show these cells likely derive from a discrete precursor in the bone marrow (BM) and are locally imprinted to produce heightened IL-1{beta} and TNF in mouse and humans. Importantly, we show that co-incident with a hyper-inflammatory phenotype, these same cells uniquely and specifically express aconitate decarboxylase (ACOD1) in response to local Toll-like receptor (TLR) and interferon (IFN) receptor signalling, to limit unrestricted cytokine production. Thus, the intestinal environment after injury instructs both inflammation and recovery specifically within a transitioning population of monocytes that are absent in health.

immunology↗

bioRxiv2022

CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration following radiation-induced injury

The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in xerostomia, or chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages are the predominant cell type in the salivary glands and are attractive therapeutic targets due to their unrivalled capacity to drive tissue repair and regeneration. Yet, the nature and role of macrophages in salivary gland homeostasis and whether or not they contribute to tissue repair/regeneration following injury is not well understood. Here, we have used single cell RNA-seq, multi-parameter flow cytometry and fluorescence microscopy to map the heterogeneity of the salivary gland macrophage compartment throughout development and following radiation-induced injury. We show that there are highly dynamic changes in the composition of the salivary gland macrophage compartment with age, in part due to changes in the ontogeny of these cells, determined using a suite of complementary fate mapping systems. A combination of mutant mice and antibody blockade demonstrates that salivary gland macrophages are dependent on CSF1, but not IL-34 or GM-CSF, for their development and maintenance. Finally, using an in vivo model of radiation-induced salivary gland injury combined with a novel Mafb-specific depletion system, we demonstrate an essential role for macrophages. Without macrophages the clearance of cells with DNA damage, and effective tissue repair following such injury, is severely comprised. Our data, therefore, indicate a strong case for exploring the therapeutic potential of manipulating macrophages in order to promote tissue repair and thus minimise salivary gland dysfunction after radiotherapy.

immunology↗

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↗