Daemen S, Gainullina A, Kalugotla G, He L, Chan MM, Beals JW, Liss KH, Klein S, Feldstein AE, Finck BN, Artyomov MN, and Schilling JD
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 TIM4 pos Kupffer cells (KCs) decrease in number, while monocyte-derived Tim4 neg 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., Competing Interests: Declaration of Interests A.E.F. is co-inventor on pending and issued patents filed by the Cleveland Clinic and UCSD that refer to the use of biomarkers and therapies in inflammatory and fibrotic disorders. Scientific Founder: Jecure Therapeutics, Elgia Therapeutics. Consultant/Advisory Board: Gilead, GSK, Merck, Ferring Pharmaceutical, Centurion BioPharma, Oppilan Pharma. The remaining authors have no interests to declare., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)