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

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Original languageEnglish
Pages (from-to)1896-1909
JournalGastroenterology
Volume149
Issue number7
Early online date5 Sep 2015
DOIs
Publication statusPublished - Dec 2015

Abstract

Background & Aims Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised following liver injury. Numbers of liver macrophages are controlled by macrophage colony stimulating factor (CSF1). We examined the prognostic significance of 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 Ccr2–/– mice; we performed fate-tracing experiments using bone marrow chimeras. We gave CSF1-Fc to mice following 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, 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 trans-differentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice following 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 following liver injury.

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