CC Chemokine Receptor 2 Promotes Recruitment of Myeloid Cells Associated with Insulin Resistance in Non-Alcoholic Fatty Liver Disease
Research output: Contribution to journal › Article › peer-review
- ChemoCentryx, Inc., Mountain View, California.
- National Institute for Health Research (NIHR), Birmingham Liver Biomedical Research Unit (BRU), and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom.
Non-alcoholic fatty liver disease (NAFLD) is a common disease, closely associated with obesity and insulin resistance. We investigated the presence of a subset of myeloid cells associated with metabolic disturbance in the liver of patients with NAFLD and a murine model of obesity-induced liver disease. Gene and protein expression in liver and serum was investigated with rt-PCR or ELISA and correlated to clinical disease. Liver-infiltrating immune cells were isolated from normal or diseased human liver for flow cytometric analysis. In animal experiments, mice were fed a high-fat diet (60% of calories from fat) for 16 weeks, or high-fat diet with 30% fructose for 32 weeks to induce steatohepatitis and fibrosis. A small molecule inhibitor of CCR2, CCX872, was administered to some mice. A subset of CD11c+CD206+ immune cells were enriched in human liver tissue, and greater infiltration was observed in NAFLD. The presence of CD11c+CD206+ myeloid cells correlated with systemic insulin resistance. CD11c+CD206+ cells expressed high levels of CCR2, and liver CCL2 expression was increased in NASH and correlated with disease activity. In mice, CCR2 inhibition reduced infiltration of liver CD11b+CD11c+F4/80+ monocytes, which are functional homologs of human CD11c+CD206+ cells, and improved liver injury and glycaemic control. A role for CCR2/CCL2 in human NAFLD has long been postulated. These data confirm a role for this chemokine/receptor axis, through mediating adipose and hepatic infiltration of myeloid cells. Inhibition of CCR2 improved hepatic inflammation and fibrosis in murine models of NAFLD. These data confirm the rationale for targeting CCR2 to treat NAFLD.
|Journal||American journal of physiology. Gastrointestinal and liver physiology|
|Early online date||8 Feb 2018|
|Publication status||E-pub ahead of print - 8 Feb 2018|
- Journal Article