Tissue resident macrophages and recruited monocyte-derived macrophages contribute to host defense but also play pathological roles in a diverse range of human diseases. Multiple macrophage phenotypes are often represented in a diseased tissue, but we lack a deep understanding of the mechanisms that control diversification. Here we use a combination of genetic, genomic, and imaging approaches to investigate the origins and epigenetic trajectories of hepatic myeloid cells during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induces striking changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death. Kupffer cell loss is compensated by gain of adjacent monocyte derived macrophages that exhibit convergent epigenomes, transcriptomes and functions. NASH-induced changes in Kupffer cell enhancers are driven by AP-1 and Egr factors that reprogram the Kupffer cell specific functions of Liver X receptors. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct programs of gene expression and corresponding phenotypes.
