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

Abstract

Background & AimsLiver 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.MethodsWe 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.ResultsSerum 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.ConclusionsSerum 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.

CRIg-expressing peritoneal macrophages are associated with disease severity in patients with cirrhosis and ascites

“…Ascites macrophages expressed both CSF1R and IL4R, with higher levels of CSF1R mRNA and surface expression (data not shown) in CRIg hi macrophages. Given that CSF-1 has been extensively developed as a therapeutic target (52) and was recently associated with good outcomes in patients with acute liver failure and demonstrated to promote liver regeneration in mice (53), CSF-1 treatment may represent a viable therapeutic strategy. Interestingly, CRIg hi macrophages exhibited a prominent IL-4 activation signature, although this was observed in both ascites macrophage populations.…”

Liver resection for cancer: New developments in prediction, prevention and management of postresectional liver failure

“…Likewise, usefulness of colony stimulating factor to accelerate post-resectional restoration of phagocytic capacity in the human setting is worth exploring [162].…”

Novel circulating- and imaging-based biomarkers to enhance the mechanistic understanding of human drug-induced liver injury

“…Hepatic macrophages are known to mediate innate immune defence mechanisms and promote regeneration (hepatocyte proliferation) following an insult to the liver; and CSF1 is known to illicit control over macrophage numbers [95]. In humans (following partial hepatectomy), elevated circulating CSF1 level can be detected and is thus associated with rapid regrowth/regeneration [95]. A publication from Stutchfield et al uncovered a correlation between serum CSF1 and patient survival in cases of ALF.…”

“…The authors suggest that serum CSF1, as a prognostic biomarker, could be a useful tool to stratify patients. Interestingly, the authors also study the effects of CSF1 administration in mice highlighting a translational aspect of the biomarker and moreover identifying CSF1 as potentially holding use in replacement therapy as treatment was able to aid in restoring innate immune function following partial hepatectomy or liver injury [95].…”