title: Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans.
abstract: Acetaminophen-induced acute liver failure (AALF) is associated with innate immunity activation, which contributes to the severity of hepatic injury and clinical outcome. A marked increase in hepatic macrophages (h-mφ) is observed in experimental models of AALF, but controversy exists regarding their role, implicating h-mφ in both aggravation and resolution of liver injury. The role of h-mφ in human AALF is virtually unexplored. We sought to investigate the role of chemokine (C-C motif) ligand 2 (CCL2) in the recruitment of circulating monocytes to the inflamed liver and to determine how the h-mφ infiltrate and liver microenvironment may contribute to tissue repair versus inflammation in AALF. We evaluated circulating monocytes, their chemokine (C-C motif) receptor 2 (CCR2) expression, and serum CCL2 levels in patients with AALF. Cell subsets and numbers of circulation-derived (MAC387+) or resident proliferating (CD68/Ki67+) h-mφ in hepatic immune infiltrates were determined by immunohistochemistry. Inflammatory cytokine levels were determined in whole and laser microdissected liver tissue by proteome array. In AALF, circulating monocytes were depleted, with the lowest levels observed in patients with adverse outcomes. CCL2 levels were high in AALF serum and hepatic tissue, and circulating monocyte subsets expressed CCR2, suggesting CCL2-dependent hepatic monocyte recruitment. Significant numbers of both MAC387+ and CD68+ h-mφ were found in AALF compared with control liver tissue with a high proportion expressing the proliferation marker Ki67. Levels of CCL2, CCL3, interleukin (IL)-6, IL-10, and transforming growth factor-β1 were significantly elevated in AALF liver tissue relative to chronic liver disease controls.
  
  
  CONCLUSIONS
  In AALF, the h-mφ population is expanded in areas of necrosis, both through proliferation of resident cells and CCL2-dependent recruitment of circulating monocytes. The presence of h-mφ within an anti-inflammatory/regenerative microenvironment indicates that they are implicated in resolution of inflammation/tissue repair processes during AALF.
authors.affiliation: Institute of Liver Studies and Cellular Biology of Inflammation, King's College London, London, United Kingdom. c.antoniades@imperial.ac.uk
authors.forename: Charalambos Gustav
authors.initials: CG
authors.lastname: Antoniades
authors.forename: Alberto
authors.initials: A
authors.lastname: Quaglia
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Taams
authors.forename: Ragai R
authors.initials: RR
authors.lastname: Mitry
authors.forename: Munther
authors.initials: M
authors.lastname: Hussain
authors.forename: Robin
authors.initials: R
authors.lastname: Abeles
authors.forename: Lucia A
authors.initials: LA
authors.lastname: Possamai
authors.forename: Matthew
authors.initials: M
authors.lastname: Bruce
authors.forename: Mark
authors.initials: M
authors.lastname: McPhail
authors.forename: Christopher
authors.initials: C
authors.lastname: Starling
authors.forename: Bart
authors.initials: B
authors.lastname: Wagner
authors.forename: Adrian
authors.initials: A
authors.lastname: Barnardo
authors.forename: Sabine
authors.initials: S
authors.lastname: Pomplun
authors.forename: Georg
authors.initials: G
authors.lastname: Auzinger
authors.forename: William
authors.initials: W
authors.lastname: Bernal
authors.forename: Nigel
authors.initials: N
authors.lastname: Heaton
authors.forename: Diego
authors.initials: D
authors.lastname: Vergani
authors.forename: Mark R
authors.initials: MR
authors.lastname: Thursz
authors.forename: Julia
authors.initials: J
authors.lastname: Wendon
mesh_terms: D000082:Acetaminophen / Q000506:poisoning*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000506:poisoning; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000473:pathology*; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3 / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054390:Receptors, CCR2 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D016753:Interleukin-10; D016209:Interleukin-8; D019394:Ki-67 Antigen; D054390:Receptors, CCR2; D053773:Transforming Growth Factor beta1; C111835:CCL2 protein, human; C515429:CCL3 protein, human; C515334:CCR2 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C508606:CXCL8 protein, human; C508609:IL10 protein, human