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糖皮质激素和白细胞介素4驱动的巨噬细胞编程之间的表观基因组和功能趋同机制

Mechanisms of Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming.

作者信息

Deochand Dinesh K, Dacic Marija, Bale Michael J, Daman Andrew W, Josefowicz Steven Z, Oliver David, Chinenov Yurii, Rogatsky Inez

机构信息

Hospital for Special Surgery Research Institute, The David Rosenzweig Genomics Center, New York, NY, USA.

Graduate Program in Physiology, Biophysics and Systems Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.

出版信息

bioRxiv. 2024 Feb 18:2024.02.16.580560. doi: 10.1101/2024.02.16.580560.

DOI:10.1101/2024.02.16.580560
PMID:38405750
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10888924/
Abstract

Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2). Glucocorticoids, widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics that M2 and M2 transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets. This core homeostatic program is enacted by transcriptional effectors KLF4 and the GC receptor, whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, many of the M2:M2-shared transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated phagocytic activity of both populations and macrophage tissue-repair properties in the murine colitis model . These findings provide a mechanistic framework for homeostatic macrophage programming by distinct signals, to better inform anti-inflammatory drug design.

摘要

巨噬细胞会根据环境线索呈现出不同的表型，其中2型细胞因子白细胞介素-4可促进组织修复的稳态状态（M2）。糖皮质激素是广泛使用的抗炎疗法，据报道可赋予类似的表型（M2），但尚不清楚如此不同的途径在功能上如何趋同。我们使用综合功能基因组学表明，M2和M2转录组存在显著重叠，这在共同基因子集和信号特异性基因子集中的染色质景观变化中得到体现。这个核心稳态程序由转录效应因子KLF4和糖皮质激素受体启动，其全基因组占据和作用通过核受体辅因子GRIP1以刺激特异性方式整合。事实上，许多M2:M2共享的转录组变化都依赖于GRIP1。同样，在小鼠结肠炎模型中，GRIP1缺失减弱了这两种细胞群体的吞噬活性以及巨噬细胞的组织修复特性。这些发现为不同信号对稳态巨噬细胞编程提供了一个机制框架，以更好地指导抗炎药物设计。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/f3d51866dd90/nihpp-2024.02.16.580560v1-f0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/c93c83d63f41/nihpp-2024.02.16.580560v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/1d8617088eac/nihpp-2024.02.16.580560v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/d73ea127af1b/nihpp-2024.02.16.580560v1-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/afd3b052c300/nihpp-2024.02.16.580560v1-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/3b921c908e5f/nihpp-2024.02.16.580560v1-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/ee84f3213b52/nihpp-2024.02.16.580560v1-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/5af4794f7192/nihpp-2024.02.16.580560v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/deb91a8c8305/nihpp-2024.02.16.580560v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/1ba641cefc93/nihpp-2024.02.16.580560v1-f0003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e51/10888924/f3d51866dd90/nihpp-2024.02.16.580560v1-f0006.jpg

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