Single cell RNAseq reveals distinct differentiation traits of COMMD10-deficient Ly6Chi monocytes in the injured liver

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE183367 | GEO | 2021/10/05

REPOSITORIES: GEO