Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.
Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.
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DOI：
10.1126/science.1251086
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发表时间：
2014-09-26
期刊：
影响因子：
--
通讯作者：
Stunnenberg HG
中科院分区：
文献类型：
--
作者：
Saeed S;Quintin J;Kerstens HH;Rao NA;Aghajanirefah A;Matarese F;Cheng SC;Ratter J;Berentsen K;van der Ent MA;Sharifi N;Janssen-Megens EM;Ter Huurne M;Mandoli A;van Schaik T;Ng A;Burden F;Downes K;Frontini M;Kumar V;Giamarellos-Bourboulis EJ;Ouwehand WH;van der Meer JW;Joosten LA;Wijmenga C;Martens JH;Xavier RJ;Logie C;Netea MG;Stunnenberg HG
单核细胞在血液中循环长达3-5天。同时，在感染或接种疫苗后观察到，耐受（免疫抑制）或训练免疫（先天免疫记忆）的免疫印记决定了单核细胞和单核细胞源性巨噬细胞的功能命运。从健康志愿者中纯化的循环单核细胞在人血清中存在的稳态M-CSF浓度下分化。在最初的24小时内，通过β-葡聚糖（BG）诱导训练免疫，而暴露于LPS模拟脓毒症后的免疫麻痹，产生内毒素诱导的耐受性。组蛋白标记H3K4me1、H3K4me3和H3K27ac的表观基因组分析、DNase I可及性和RNA测序在实验开始时（离体单核细胞）和体外培养6天结束时（巨噬细胞）进行。与单核细胞（Mo）相比，naïve巨噬细胞（Mf）表现出重塑的代谢酶库和减弱的先天炎症途径；很可能是产生功能性组织巨噬细胞所必需的。表观遗传分析发现约8000个动态区域与约11000个DNase I超敏感位点相关。组蛋白乙酰化的变化确定了大多数动态事件。此外，这些差异组蛋白标记区域显示了单核细胞中已经存在的一定程度的DNase I可及性。H3K4me1标记在远端调控区与H3K27ac沉积平行增加；H3K4me1标记即使在H3K27ac缺失后仍然存在，标志着退役的调控元件。β-葡聚糖启动特异性诱导了约3000个远端调控元件，而lps耐受仅诱导了约500个远端调控区域的H3K27ac。在转录水平上，我们确定了单核细胞向巨噬细胞分化过程中的共调控基因模块，以及训练细胞和耐受细胞之间的不一致模块。这些表明训练可能涉及naïve巨噬细胞中表达的模块的表达增加，包括编码代谢酶的基因。另一方面，内毒素耐受涉及单核细胞中比naïve巨噬细胞中更活跃的基因模块。大约12%的已知人转录因子在巨噬细胞分化、训练和耐受过程中表现出表达变异。我们还在条件特异性动态表观基因组区域的DNase I超敏感位点观察到转录因子基序，这意味着训练和耐受巨噬细胞的表观遗传和转录程序需要特定的转录因子。最后，我们的分析和功能验证表明，在体外和体内致命白色念珠菌感染模型中，抑制cAMP的产生阻断了训练免疫，取消了训练免疫的保护作用。我们记录了单核细胞到巨噬细胞分化和训练免疫的免疫途径的表观遗传调控的重要性。这些动态的表观遗传因素可能会提示调节先天免疫的潜在药理靶点。总之，我们揭示了单核细胞分化为巨噬细胞的表观遗传和转录程序，这些程序区分了耐受型和训练型巨噬细胞表型，为进一步理解和操纵免疫介导的反应提供了资源。
Monocytes circulate in the bloodstream for up to 3–5 days. Concomitantly, immunological imprinting of either tolerance (immunosuppression) or trained immunity (innate immune memory) determines the functional fate of monocytes and monocyte-derived macrophages, as observed after infection or vaccination. Purified circulating monocytes from healthy volunteers were differentiated under the homeostatic M-CSF concentrations present in human serum. During the first 24 hours, trained immunity was induced by β-glucan (BG) priming, while post-sepsis immunoparalysis was mimicked by exposure to LPS, generating endotoxin-induced tolerance. Epigenomic profiling of the histone marks H3K4me1, H3K4me3 and H3K27ac, DNase I accessibility and RNA sequencing were performed at both the start of the experiment (ex vivo monocytes) and at the end of the six days of in vitro culture (macrophages). Compared to monocytes (Mo), naïve macrophages (Mf) display a remodeled metabolic enzyme repertoire and attenuated innate inflammatory pathways; most likely necessary to generate functional tissue macrophages. Epigenetic profiling uncovered ~8000 dynamic regions associated with ~11000 DNase I hypersensitive sites. Changes in histone acetylation identified most dynamic events. Furthermore, these regions of differential histone marks displayed some degree of DNase I accessibility that was already present in monocytes. H3K4me1 mark increased in parallel with de novo H3K27ac deposition at distal regulatory regions; H3K4me1 mark remained even after the loss of H3K27ac, marking decommissioned regulatory elements. β-glucan priming specifically induced ~3000 distal regulatory elements, whereas LPS-tolerization uniquely induced H3K27ac at ~500 distal regulatory regions. At the transcriptional level, we identified co-regulated gene modules during monocyte to macrophage differentiation, as well as discordant modules between trained and tolerized cells. These indicate that training likely involves an increased expression of modules expressed in naïve macrophages, including genes that code for metabolic enzymes. On the other hand, endotoxin tolerance involves gene modules that are more active in monocytes than in naïve macrophages. About 12% of known human transcription factors display variation in expression during macrophage differentiation, training and tolerance. We also observed transcription factor motifs in DNase I hypersensitive sites at condition-specific dynamic epigenomic regions, implying that specific transcription factors are required for trained and tolerized macrophage epigenetic and transcriptional programs. Finally, our analyses and functional validation indicate that the inhibition of cAMP generation blocked trained immunity in vitro and during an in vivo model of lethal C. albicans infection, abolishing the protective effects of trained immunity. We documented the importance of epigenetic regulation of the immunological pathways underlying monocyte-to-macrophage differentiation and trained immunity. These dynamic epigenetic elements may inform on potential pharmacological targets that modulate innate immunity. Altogether, we uncovered the epigenetic and transcriptional programs of monocyte differentiation to macrophages that distinguish tolerant and trained macrophage phenotypes, providing a resource to further understand and manipulate immune-mediated responses.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
20.3
作者：
Hashimoto, S;Suzuki, T;Matsushima, K
通讯作者：
Matsushima, K
影响因子：
64.8
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan
影响因子：
3.5
作者：
Dong C;Zhao G;Zhong M;Yue Y;Wu L;Xiong S
通讯作者：
Xiong S
影响因子：
3.1
作者：
Bagley, KC;Abdelwahab, SF;Lewis, GK
通讯作者：
Lewis, GK