Understanding the Heterogeneity of Resident Liver Macrophages

Abstract

Resident tissue macrophages (RTMs) are cells with a high functional plasticity assuming pleiotropic roles in their tissue of residence, from clearance of dead cells and metabolic sensing in steady state to cytokine production and tissue repair during inflammation. The liver has long been considered as only populated by Kupffer cells (KCs), a macrophage population assumed to be in charge of all of these functions. However, we know now that KCs are not the only macrophage population in the liver, that recently was shown to contain also capsular macrophages, monocyte-derived macrophages as well as recruited peritoneal macrophages inherited from previous inflammatory events. These macrophages exhibit different origins, time of establishing residence and locations in the liver, with both ontogenical and environmental factors shaping their identity and functions. Furthermore, liver macrophages reside in a complex environment with a pronounced metabolic zonation. Here, we briefly discuss how these intrinsic and extrinsic factors influence macrophage biology and liver physiology in general. We notably focus on how the recent advances of single cell transcriptomic approaches are changing our understanding of liver macrophages and diseases.

GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease

“…Speculation regarding potential macrophage engulfment of exogenous PBs is complicated by the heterogeneous roles of these cells in local and systemic immune responses. 33 Our data suggest that the liver macrophage PBs do not, at least in large part, originate in hepatocytes, because otherwise the significant reduction in hepatocyte glycogen by PPP1R3C deficiency should have impacted macrophage PB quantities. Interrogation of the reparative and/or pathogenic roles of the immune response in GSD IV, and particularly in the nervous system in APBD, would be valuable.…”

“…Macrophages have been shown to actively metabolize glycogen, with increased synthesis and Gys1 expression regulating their inflammatory phenotype, 32 however, it remains unclear if GBE1 deficiency in this metabolic context would lead to PB formation. Speculation regarding potential macrophage engulfment of exogenous PBs is complicated by the heterogeneous roles of these cells in local and systemic immune responses 33 . Our data suggest that the liver macrophage PBs do not, at least in large part, originate in hepatocytes, because otherwise the significant reduction in hepatocyte glycogen by PPP1R3C deficiency should have impacted macrophage PB quantities.…”

Liver Abnormalities after Elimination of HCV Infection: Persistent Epigenetic and Immunological Perturbations Post-Cure

“…The abundance of monocyte-derived cells is increased after Kupffer cell depletion, an aspect of emergency myelopoiesis. Two Kupffer cell subsets were resolved in single-cell RNA sequencing analyses of unmanipulated mouse liver [ 48 ], and two broadly equivalent subsets were resolved in human liver, both by single cell RNA sequencing [ 49 , 50 ] and by flow cytometry [ 51 ]. Current research does not address whether HCV modulates the activity of one or both Kupffer cell subsets.…”

The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG

“…Liver functions as the main hematopoietic tissue during early stage of mammal's prenatal ontogeny (5). In adults, liver also provides a niche for the self-renewable tissue resident macrophages, Kupffer cells, (6), indicating a supportive niche for cell maintenance in liver. Recent studies demonstrate a chemo-protective niche for leukemia stem cells (LSCs) in adipose tissue (7), suggesting that extramedullary niches can play a key role in disease development and persistence, and consequently important targeting sites.…”