Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis
Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis
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DOI：
10.1016/j.immuni.2020.04.001
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发表时间：
2020-06-16
期刊：
影响因子：
32.4
通讯作者：
Glass, Christopher K.
中科院分区：
文献类型：
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作者：
Seidman, Jason S.;Troutman, Ty D.;Glass, Christopher K.
组织驻留和招募的巨噬细胞有助于宿主防御和病理。多种巨噬细胞表型在病变组织中有代表性，但我们对控制多样化的机制缺乏深入的了解。在这里，我们研究了饮食诱导的非酒精性脂肪性肝炎（NASH）过程中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著变化，导致库普弗细胞身份的部分丧失、Trem 2和Cd 9表达的诱导以及细胞死亡。库普弗细胞丧失通过获得相邻单核细胞衍生的巨噬细胞来补偿，所述巨噬细胞表现出会聚的表观基因组、转录组和功能。NASH诱导的库普弗细胞增强子的变化由AP-1和EGR驱动，其重新编程库普弗细胞身份和存活所需的LXR功能，以替代驱动瘢痕相关的巨噬细胞表型。这些发现揭示了疾病相关的环境信号指导居民和招募的巨噬细胞获得不同的基因表达程序和相应功能的机制。
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.