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Gastroenterology. 2015 Dec;149(7):1896-1909.e14. doi: 10.1053/j.gastro.2015.08.053. Epub 2015 Sep 5.

CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure.

Author information

1
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom; Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
2
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Edinburgh, Edinburgh, United Kingdom.
3
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
4
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.
5
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
6
MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
7
Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
8
Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
9
National Poisons Information Service Edinburgh, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, United Kingdom.
10
MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, United Kingdom.
11
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: stuart.forbes@ed.ac.uk.

Abstract

BACKGROUND & AIMS:

Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice.

METHODS:

We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles.

RESULTS:

Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells.

CONCLUSIONS:

Serum CSF1 appears to be a prognostic marker for patients with acute liver injury. CSF1 might be developed as a therapeutic agent to restore innate immune function after liver injury.

KEYWORDS:

Clearance; Drug-Induced Liver Damage; Immune Response; M-CSF

Comment in

PMID:
26344055
PMCID:
PMC4672154
DOI:
10.1053/j.gastro.2015.08.053
[Indexed for MEDLINE]
Free PMC Article

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