Non-alcoholic steatohepatitis induces transient changes within the liver macrophage pool

Kupffer cells (KCs) and monocyte-derived macrophages are implicated in non-alcoholic steatohepatitis (NASH) pathogenesis but their functions remain unclear due to the lack of specific markers to distinguish between the different cell types. Additionally, it is unclear if multiple subsets of KCs are present during NASH. Here, we characterized the liver macrophage subsets during methionine/choline deficient (MCD) diet-induced NASH and recovery. We observed a significant reduced contribution of Ly6C^loClec4F⁺Tim4⁺KCs to the hepatic macrophage pool in MCD fed mice, which normalized during recovery. Ly6C^loClec4F^-Tim4^- monocyte-derived macrophages increased during MCD feeding and returned to baseline during recovery. Ly6C^loClec4F⁺Tim4^- monocyte-derived KCs developed during initial recovery but did not self-renew as their numbers were reduced after full recovery. Initial recovery from MCD diet feeding was further characterized by increased proportions of Ki-67⁺ proliferating KCs. In conclusion, the hepatic macrophage pool undergoes substantial albeit transient changes during NASH and recovery, with the KC pool being maintained by proliferation and differentiation of short-lived monocyte-derived KCs.