Dynamic Shifts in the Composition of Resident and Recruited Macrophages Influence Tissue Remodeling in NASH
Sabine Daemen,
Anastasiia Gainullina,
Gowri Kalugotla,
Li He,
Mandy M. Chan,
Joseph W. Beals,
Kim H. Liss,
Samuel Klein,
Ariel E. Feldstein,
Brian N. Finck,
Maxim N. Artyomov,
Joel D. Schilling
Affiliations
Sabine Daemen
Diabetes Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Anastasiia Gainullina
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; ITMO University, Saint Petersburg, Russia
Gowri Kalugotla
Diabetes Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Li He
Diabetes Research Center, Washington University School of Medicine, St. Louis, MO, USA
Mandy M. Chan
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Joseph W. Beals
Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
Kim H. Liss
Diabetes Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
Samuel Klein
Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
Ariel E. Feldstein
Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
Brian N. Finck
Diabetes Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
Maxim N. Artyomov
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Joel D. Schilling
Diabetes Research Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA; Corresponding author
Summary: Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM4pos Kupffer cells (KCs) decrease in number, while monocyte-derived Tim4neg macrophages accumulate. In concert, monocyte-derived infiltrating macrophages enter the liver and consist of a transitional subset that expresses Cx3cr1/Ccr2 and a second subset characterized by expression of Trem2, Cd63, Cd9, and Gpmnb; markers ascribed to lipid-associated macrophages (LAMs). The Cx3cr1/Ccr2-expressing macrophages, referred to as C-LAMs, localize to macrophage aggregates and hepatic crown-like structures (hCLSs) in the steatotic liver. In C-motif chemokine receptor 2 (Ccr2)-deficient mice, C-LAMs fail to appear in the liver, and this prevents hCLS formation, reduces LAM numbers, and increases liver fibrosis. Taken together, our data reveal dynamic changes in liver macrophage subsets during the pathogenesis of NASH and link these shifts to pathologic tissue remodeling.
