Macrophage-mediated inflammation is critical in the pathogenesis of NASH. T-cell immunoglobulin domain and mucin domain-4 (TIM-4) is selectively expressed on antigen-presenting cells and modulates various immune responses. However, the role of TIM-4 expressed by Kupffer cells in liver fibrosis remains unclear. In this article, S. Daemen et al. (Washington University School of Medicine, St. Louis, MI, USA) describe that, with high-fat, high-sucrose-diet feeding, mature TIM4pos Kupffer cells decrease in number, while Tim4neg macrophages, which are monocyte-derived, accumulate. Taken together, their data reveal dynamic changes in liver macrophage subsets during the pathogenesis of NASH and link these shifts to pathologic tissue remodeling.