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

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.

Regulation of adipocyte 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) by CCAAT/enhancer-binding protein (C/EBP) ß isoforms, LIP and LAP.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyses intracellular regeneration of active glucocorticoids, notably in liver and adipose tissue. 11ß-HSD1 is increased selectively in adipose tissue in human obesity, a change implicated in the pathogenesis of metabolic syndrome. With high fat (HF)-feeding, adipose tissue 11ß-HSD1 is down-regulated in mice, plausibly to counteract metabolic disease. Transcription of 11ß-HSD1 is directly regulated by members of the CCAAT/enhancer binding protein (C/EBP) family. Here we show that while total C/EBPß in adipose tissue is unaltered by HF diet, the ratio of the C/EBPß isoforms liver-enriched inhibitor protein (LIP) and liver-enriched activator protein (LAP) (C/EBPß-LIP:LAP) is increased in subcutaneous adipose. This may cause changes in 11ß-HSD1 expression since genetically modified C/EBPß((+/L)) mice, with increased C/EBPß-LIP:LAP ratio, have decreased subcutaneous adipose 11ß-HSD1 mRNA levels, whereas C/EBPß(ΔuORF) mice, with decreased C/EBPß-LIP:LAP ratio, show increased subcutaneous adipose 11ß-HSD1. C/EBPß-LIP:LAP ratio is regulated by endoplasmic reticulum (ER) stress and mTOR signalling, both of which are altered in obesity. In 3T3-L1 adipocytes, 11ß-HSD1 mRNA levels were down-regulated following induction of ER stress by tunicamycin but were up-regulated following inhibition of mTOR by rapamycin. These data point to a central role for C/EBPß and its processing to LIP and LAP in transcriptional regulation of 11ß-HSD1 in adipose tissue. Down-regulation of 11ß-HSD1 by increased C/EBPß-LIP:LAP in adipocytes may be part of a nutrient-sensing mechanism counteracting nutritional stress generated by HF diet.