Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induced significant 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 was compensated by gain of adjacent monocyte-derived macrophages that exhibited convergent epigenomes, transcriptomes, and functions. NASH-induced changes in Kupffer cell enhancers were driven by AP-1 and EGR that reprogrammed LXR functions required for Kupffer cell identity and survival to instead drive a scar-associated macrophage phenotype. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct gene expression programs and corresponding functions.

组织驻留和招募的巨噬细胞有助于宿主防御和病理学。病变组织中存在多种巨噬细胞表型，但我们对控制多样化的机制缺乏深入了解。在这里，我们研究了饮食诱导的非酒精性脂肪性肝炎 (NASH) 期间肝巨噬细胞的起源和表观遗传轨迹。NASH 饮食诱导库普弗细胞增强子和基因表达的显着变化，导致库普弗细胞身份的部分丧失，Trem2和Cd9 的诱导表达和细胞死亡。枯否细胞的损失通过邻近单核细胞衍生的巨噬细胞的获得来补偿，这些巨噬细胞表现出收敛的表观基因组、转录组和功能。NASH 诱导的库普弗细胞增强子的变化是由 AP-1 和 EGR 驱动的，它们重新编程库普弗细胞身份和存活所需的 LXR 功能，转而驱动疤痕相关的巨噬细胞表型。这些发现揭示了疾病相关环境信号指示常驻和募集巨噬细胞获得不同基因表达程序和相应功能的机制。