title: Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2.
abstract: Inflammatory cell infiltration in the liver is a hallmark of nonalcoholic steatohepatitis (NASH). The chemokine-chemokine receptor interaction induces inflammatory cell recruitment. CC-chemokine receptor (CCR)2 is expressed on hepatic macrophages and hepatic stellate cells. This study aims to investigate the therapeutic potential of CCR2 to NASH. Twenty-two weeks on a choline-deficient amino acid-defined (CDAA) diet induced steatosis, inflammatory cell infiltration, and liver fibrosis with increased CCR2 and monocyte chemoattractant protein (MCP)-1 expression in the wild-type livers. The infiltrated macrophages expressed CD68, CCR2, and a marker of bone marrow-derived monocytes, Ly6C. CCR2(-/-) mice had less steatosis, inflammatory cell infiltration, and fibrosis, and hepatic macrophages expressing CD68 and Ly6C were decreased. Toll-like receptor (TLR)4(-/-), TLR9(-/-), and MyD88(-/-) mice had reduced hepatic macrophage infiltration with decreased MCP-1 and CCR2 expression because TLR signaling is a potent inducer of MCP-1. To assess the role of Kupffer cells at the onset of NASH, Kupffer cells were depleted by liposomal clodronate. The Kupffer cell depletion ameliorated steatohepatitis with a decrease in the MCP-1 expression and recruitment of Ly6C-expressing macrophages at the onset of NASH. Finally, to test the therapeutic potential of targeting CCR2, a CCR2 inhibitor was administered to mice on a CDAA diet. The pharmaceutical inhibition of CCR2 prevented infiltration of the Ly6C-positive macrophages, resulting in an inhibition of liver inflammation and fibrosis. We concluded that CCR2 and Kupffer cells contribute to the progression of NASH by recruiting bone marrow-derived monocytes.
authors.affiliation: Department of Medicine, School of Medicine, University of California San Diego, La Jolla, USA.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Miura
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Hirohide
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D004032:Diet; D005234:Fatty Liver / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000150:complications / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000378:metabolism*
chemical_list: C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2