1. Roles of CCR2 and CCR5 for Hepatic Macrophage Polarization in Mice With Liver Parenchymal Cell-Specific NEMO Deletion
- Author
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Klaudia Theresa Warzecha, Sebastian Huss, Ralf Weiskirchen, Tom Luedde, Matthias Bartneck, Marlene Kohlhepp, Christiane Koppe, Frank Tacke, Christian Trautwein, and Viktor Fech
- Subjects
Liver Cirrhosis ,Male ,0301 basic medicine ,CCR2 ,Carcinogenesis ,MoMF, monocyte-derived macrophage ,PDGF, platelet-derived growth factor ,Hepatitis ,Mice ,Liver disease ,Chemokine receptor ,0302 clinical medicine ,Fibrosis ,Macrophage ,BMDM, bone marrow-derived macrophages ,Cells, Cultured ,Original Research ,Mice, Knockout ,Liver injury ,TNF, tumor necrosis factor ,Liver Neoplasms ,Intracellular Signaling Peptides and Proteins ,CCL, CC motif chemokine ,Gastroenterology ,HSC, hepatic stellate cell ,mRNA, messenger RNA ,CCR, CC-chemokine receptor ,Liver ,Disease Progression ,LPS, lipopolysaccharide ,030211 gastroenterology & hepatology ,Liver cancer ,NASH, nonalcoholic steatohepatitis ,NK, natural killer ,Liver Cancer ,Receptors, CCR5 ,Receptors, CCR2 ,Primary Cell Culture ,PPAR, Peroxisome proliferator-activated receptor ,03 medical and health sciences ,ALT, alanine aminotransferase ,TGF-β, transforming growth factor beta ,medicine ,Animals ,Humans ,KC, Kupffer cell ,KO, knockout ,LPC, liver parenchymal cell ,Hepatology ,SREBP, sterol-regulatory element binding protein ,business.industry ,Macrophages ,Cell Therapy ,medicine.disease ,WT, wild-type ,IL, interleukin ,Disease Models, Animal ,030104 developmental biology ,CLL, clodronate-loaded liposome ,IFNγ, interferon gamma ,Hepatocytes ,Hepatic stellate cell ,Cancer research ,NAFLD, nonalcoholic fatty liver disease ,business ,NEMO, nuclear factor kappa B essential modulator - Abstract
Background & aims Macrophages are key regulators of inflammation and cancer promotion in the liver, and their recruitment and activation is linked to chemokine receptor signaling. However, the exact roles of the chemokine receptors CCR2 and CCR5 for macrophage functions in the liver is obscure. Methods To study CCR2 and CCR5 in inflammatory liver injury, we used mice with a hepatocyte-specific knock-out of the nuclear factor κB (NF-κB) essential modulator (NEMO), termed NEMOLPC-KO mice, and generated NEMOLPC-KOCcr2-/- and NEMOLPC-KOCcr5-/- mice. NEMOLPC-KO mice develop hepatitis and fibrosis after two and liver tumors after six months. Results We found that both CCR2 and CCR5 deficiency led to reduced fibrosis, while CCR5 deficiency increased steatosis and tumor burden in NEMOLPC-KO mice. CCR2 was required for recruitment of hepatic macrophages, whereas CCR5 promoted stellate cell activation. The reduction of monocytes and macrophages by either anti-Gr1 antibody or clodronate-loaded liposomes (CLL), but not of CD8+ T cells or NK cells, significantly aggravated liver injury in NEMOLPC-KO mice and was further increased in NEMOLPC-KOCcr5-/- mice. CLL-induced liver injury was dampened by the adoptive transfer of ex vivo generated macrophages, whereas the adoptive transfer of control CD115+ immature monocytes or B cells did not reduce liver injury. Conclusions Although CCR2 and CCR5 principally promote liver fibrosis, they exert differential functions on hepatic macrophages during liver disease progression in NEMOLPC-KO mice. While CCR2 controls the recruitment of monocytes to injured livers, CCR5-dependent functions of liver macrophages limit hepatic injury, thereby reducing steatosis and hepatocarcinogenesis., Graphical abstract
- Published
- 2021