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Phenotyping of macrophages derived from TpMos and Mature Ly6Chi monocytes

ABSTRACT: Monocytes are integral cells of the innate immune system that play important roles in host defence and tissue repair. It is well established that monocytes are derived from the common monocyte progenitor (cMoP) in the bone marrow (BM) before giving rise to Ly6Chi mature monocytes that enter the circulation. However, our lab has discovered that BM Ly6Chi monocytes are not homogenous, and consist of two subpopulations (CXCR4hi and CXCR4lo) in both mice and humans. In particular, the CXCR4hi subset (termed transitional pre-monocyte (TpMo) population) actively proliferates in the BM and matures into the CXCR4lo subset, which represents mature Ly6Chi monocytes. Nevertheless, how this TpMo population may behave beyond their precursor role in the BM remains undefined. While TpMos have been shown to be strictly immobilized in the BM in the steady state, our preliminary data revealed the mobilization of TpMos into the circulation during sepsis. Furthermore, TpMos were found to give rise to more macrophages than mature Ly6Chi monocytes. Our data hence suggests a critical peripheral role for TpMos that may implicate the outcome of sepsis and possible potential implications in future therapies associated with monocytes. Based on our preliminary findings, we aim to have a better understanding of these monocyte subsets and how they are transcriptionally distinct when they have become macrophages. In particular, we would like to determine if TpMo-derived macrophages are less inflammatory compared to mature monocyte-derived macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE192449 | GEO | 2022/03/09

REPOSITORIES: GEO

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Project description:Hepatic macrophages play a central role in the initiation, progression and resolution of various liver diseases. Specifically, infiltrating Ly6Chi monocytes and their-derived macrophage (MoMFs) descendants prevail in acute or chronic liver injury, display marked transcriptional variance and provide crucial functional plasticity. A specific example of MoMFs are lipid associated macrophages (LAMs) involved in progression of metabolic liver disease (Remmerie et al., 2020). Recent studies have uncovered binary developmental trajectories of monocytes in the BM with Neutrophil-like (NeuMo) and dendritic cell (DC)-like (DCMo) monocytes (Weinreb et al., 2020; Yanez et al., 2017), hence further challenging our current comprehension of macrophage heterogeneity in the diseased liver. Yet, the molecular factors regulating their inflammatory versus restorative activity remains enigmatic. The COMMD (copper metabolism MURR1 domain) family includes 10 evolutionarily conserved proteins. Functions of COMMD proteins are still being defined, but they seem to play non-redundant roles in regulating transcription and protein trafficking. Utilizing conditional COMMD10 knockout mice we uncovered a role for COMMD10 in limiting inflammasome activation in Ly6Chi monocytes during experimental sepsis and colitis (Mouhadeb et al., 2018), and in supporting phagolysosomal biogenesis and maturation in KCs and BM-derived macrophages infected with Staphylococcus aureus (Ben Shlomo et al., 2019). Hence, these studies mark COMMD10 as a candidate mediator of monocyte and macrophage fate and immune responses. Here we studeis the effect of COMMD10-deficiency on Ly6Chi monocyte differentiation and inflammatory behaviour in the injured liver, using an acute model of acetaminophen-induced liver injury (AILI). Single cell RNAseq analysis of sorted Ly6Chi monocytes, comparing between COMMD10+ and COMMD10-deficient cells, revealed increased differentiation bias of Ly6Chi monocytes towards NeuMo and LAM differentiation fates. Collectively, COMMD10 appears as an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.

Project description:Hepatic macrophages play a central role in the initiation, progression and resolution of various liver diseases. Specifically, infiltrating Ly6Chi monocytes and their-derived macrophage (MoMFs) descendants prevail in acute or chronic liver injury, display marked transcriptional variance and provide crucial functional plasticity. A specific example of MoMFs are lipid associated macrophages (LAMs) involved in progression of metabolic liver disease (Remmerie et al., 2020). Recent studies have uncovered binary developmental trajectories of monocytes in the BM with Neutrophil-like (NeuMo) and dendritic cell (DC)-like (DCMo) monocytes (Weinreb et al., 2020; Yanez et al., 2017), hence further challenging our current comprehension of macrophage heterogeneity in the diseased liver. Yet, the molecular factors regulating their inflammatory versus restorative activity remains enigmatic. The COMMD (copper metabolism MURR1 domain) family includes 10 evolutionarily conserved proteins. Functions of COMMD proteins are still being defined, but they seem to play non-redundant roles in regulating transcription and protein trafficking. Utilizing conditional COMMD10 knockout mice we uncovered a role for COMMD10 in limiting inflammasome activation in Ly6Chi monocytes during experimental sepsis and colitis (Mouhadeb et al., 2018), and in supporting phagolysosomal biogenesis and maturation in KCs and BM-derived macrophages infected with Staphylococcus aureus (Ben Shlomo et al., 2019). Hence, these studies mark COMMD10 as a candidate mediator of monocyte and macrophage fate and immune responses. Here we studeid the effect of COMMD10-deficiency on Ly6Chi monocyte differentiation and inflammatory behaviour in the injured liver, using an acute model of acetaminophen-induced liver injury (AILI). Bulk RNAseq analysis of sorted Ly6Chi monocytes, comparing between COMMD10+ and COMMD10-deficient cells, revealed an increased differentiation bias of Ly6Chi monocytes towards NeuMo and LAM differentiation fates. Collectively, COMMD10 appears as an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.

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Phenotyping of macrophages derived from TpMos and Mature Ly6Chi monocytes

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