Elsevier

Journal of Hepatology

Volume 60, Issue 5, May 2014, Pages 1090-1096
Journal of Hepatology

Clinical Application of Basic Science
Macrophage heterogeneity in liver injury and fibrosis

https://doi.org/10.1016/j.jhep.2013.12.025Get rights and content
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open access

Summary

Hepatic macrophages are central in the pathogenesis of chronic liver injury and have been proposed as potential targets in combatting fibrosis. Recent experimental studies in animal models revealed that hepatic macrophages are a remarkably heterogeneous population of immune cells that fulfill diverse functions in homeostasis, disease progression, and regression from injury. These range from clearance of pathogens or cellular debris and maintenance of immunological tolerance in steady state conditions; central roles in initiating and perpetuating inflammation in response to injury; promoting liver fibrosis via activating hepatic stellate cells in chronic liver damage; and, finally, resolution of inflammation and fibrosis by degradation of extracellular matrix and release of anti-inflammatory cytokines. Cellular heterogeneity in the liver is partly explained by the origin of macrophages. Hepatic macrophages can either arise from circulating monocytes, which are recruited to the injured liver via chemokine signals, or from self-renewing embryo-derived local macrophages, termed Kupffer cells. Kupffer cells appear essential for sensing tissue injury and initiating inflammatory responses, while infiltrating Ly-6C+ monocyte-derived macrophages are linked to chronic inflammation and fibrogenesis. In addition, proliferation of local or recruited macrophages may possibly further contribute to their accumulation in injured liver. During fibrosis regression, monocyte-derived cells differentiate into Ly-6C (Ly6C, Gr1) low expressing ‘restorative’ macrophages and promote resolution from injury. Understanding the mechanisms that regulate hepatic macrophage heterogeneity, either by monocyte subset recruitment, by promoting restorative macrophage polarization or by impacting distinctive macrophage effector functions, may help to develop novel macrophage subset-targeted therapies for liver injury and fibrosis.

Abbreviations

CCL
C-C motif chemokine ligand
CCl4
carbon tetrachloride
CCR
C-C motif chemokine receptor
CSF
colony stimulating factor
CX3CL1
fractalkine
CX3CR1
fractalkine receptor
DAMPs
damage-associated molecular pattern molecules
FACS
fluorescence activated cell sorter
HSC
hepatic stellate cell
IFN
interferon
IL
interleukin
iNOS
inducible nitric oxide synthase
LPS
lipopolysaccharide
Ly-6C
monocyte/macrophage differentiation antigen
M1/M2
macrophage polarization status 1/2
MMP
matrix metalloproteinases
NF
nuclear factor
PAMPs
pathogen-associated molecular patterns
PDGF
platelet derived growth factor
TGF
transforming growth factor
TNF
tumor necrosis factor

Keywords

Macrophage
Monocyte
Liver fibrosis
Liver inflammation
Chemokines

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