Monocyte subsets in human liver disease show distinct... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics

Liaskou, Evaggelia1; Zimmermann, Henning W.1,2; Li, Ka-Kit1; Oo, Ye H.1; Suresh, Shankar1; Stamataki, Zania1; Qureshi, Omar3; Lalor, Patricia F.1; Shaw, Jean1; Syn, Wing-kin1,4,5; Curbishley, Stuart M.1; Adams, David H.1,*,1

1Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom

2Medical Department III, University Hospital of Aachen, Germany

3Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom

4The Institute of Hepatology, Regeneration and Repair Group, London, United Kingdom

5Department of Physiology, University of the Basque Country, Bilbao, Spain

*Professor of Hepatology, Centre for Liver Research, 5th Floor 1BR, University of Birmingham, Edgbaston, Birmingham B152TT, United Kingdom

Email: [email protected]

Received 27 March 2012; Accepted 1 August 2012

Published online 4 December 2012.

2Potential conflict of interest: Nothing to report.

1fax: (44)-121-415-8701

Abstract

Liver fibrosis is a wound healing response to chronic liver injury and inflammation in which macrophages and infiltrating monocytes participate in both the development and resolution phase. In humans, three monocyte subsets have been identified: the classical CD14++CD16−, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes. We studied the phenotype and function of these monocyte subsets in peripheral blood and liver tissue from patients with chronic inflammatory and fibrotic liver diseases. The frequency of intrahepatic monocytes increased in disease compared with control liver tissue, and in both nondiseased and diseased livers there was a higher frequency of CD14++CD16+ cells with blood. Our data suggest two nonexclusive mechanisms of CD14++CD16+ accumulation in the inflamed liver: (1) recruitment from blood, because more than twice as many CD14++CD16+ monocytes underwent transendothelial migration through hepatic endothelial cells compared with CD14++CD16− cells; and (2) local differentiation from CD14++CD16− classical monocytes in response to transforming growth factor β and interleukin (IL)-10. Intrahepatic CD14++CD16+ cells expressed both macrophage and dendritic cell markers but showed high levels of phagocytic activity, antigen presentation, and T cell proliferation and secreted proinflammatory (tumor necrosis factor α, IL-6, IL-8, IL-1β) and profibrogenic cytokines (IL-13), chemokines (CCL1, CCL2, CCL3, CCL5), and growth factors (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor), consistent with a role in the wound healing response. Conclusion: Intermediate CD14++CD16+ monocytes preferentially accumulate in chronically inflamed human liver as a consequence of enhanced recruitment from blood and local differentiation from classical CD14++CD16− monocytes. Their phagocytic potential and ability to secrete inflammatory and profibrogenic cytokines suggests they play an important role in hepatic fibrogenesis. (Hepatology 2013)

Abbreviations: ALD, alcoholic liver disease; CFSE, carboxyfluorescein succinimidyl ester; DC, dendritic cell; FACS, fluorescence-activated cell sorting; HSC, hepatic stellate cell; HSEC, hepatic sinusoidal endothelial cell; IFNγ, interferon-γ; IL, interleukin; MNC, mononuclear cell; NASH, nonalcoholic steatohepatitis; NK, natural killer; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; RPMI-1640, Roswell Park Memorial Institute 1640 medium; TGFβ, transforming growth factor β; Th, T helper; TNFα, tumor necrosis factor α.