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Nrf2是稳态和脓毒症中髓源性抑制细胞代谢重编程的核心调节因子。

Nrf2 Is a Central Regulator of Metabolic Reprogramming of Myeloid-Derived Suppressor Cells in Steady State and Sepsis.

作者信息

Ohl Kim, Fragoulis Athanassios, Klemm Patricia, Baumeister Julian, Klock Wiebke, Verjans Eva, Böll Svenja, Möllmann Julia, Lehrke Michael, Costa Ivan, Denecke Bernd, Schippers Angela, Roth Johannes, Wagner Norbert, Wruck Christoph, Tenbrock Klaus

机构信息

Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.

Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen, Aachen, Germany.

出版信息

Front Immunol. 2018 Jul 6;9:1552. doi: 10.3389/fimmu.2018.01552. eCollection 2018.

DOI:10.3389/fimmu.2018.01552
PMID:30034396
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6043652/
Abstract

Arising in inflammatory conditions, myeloid-derived suppressor cells (MDSCs) are constantly confronted with intracellular and extracellular reactive oxygen species molecules and oxidative stress. Generating mice with a constitutive activation of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) we show a pivotal role of the antioxidant stress defense for development of these immune-modulatory cells. These mice are characterized by a massive increase of splenic CD11bGr-1 cells, which exhibit typical suppressive characteristics of MDSCs. Whole transcriptome analysis revealed Nrf2-dependent activation of cell cycle and metabolic pathways, which resemble pathways in CD11bGr-1 MDSCs expanded by LPS exposure. Constitutive Nrf2 activation thereby regulates activation and balance between glycolysis and mitochondrial metabolism and hence expansion of highly suppressive MDSCs, which mediate protection in LPS-induced sepsis. Our study establishes Nrf2 as key regulator of MDSCs and acquired tolerance against LPS-induced sepsis.

摘要

髓系来源的抑制细胞（MDSCs）产生于炎症条件下，不断面临细胞内和细胞外的活性氧分子以及氧化应激。通过构建核因子（红系衍生2）样2（Nrf2）持续激活的小鼠，我们发现抗氧化应激防御在这些免疫调节细胞的发育中起关键作用。这些小鼠的特征是脾脏CD11bGr-1细胞大量增加，这些细胞表现出MDSCs的典型抑制特性。全转录组分析揭示了细胞周期和代谢途径的Nrf2依赖性激活，这类似于通过暴露于LPS而扩增的CD11bGr-1 MDSCs中的途径。组成性Nrf2激活从而调节糖酵解和线粒体代谢之间的激活和平衡，进而调节高抑制性MDSCs的扩增，这些细胞在LPS诱导的脓毒症中发挥保护作用。我们的研究确立了Nrf2作为MDSCs的关键调节因子以及对LPS诱导的脓毒症的获得性耐受性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/30aff605c2c3/fimmu-09-01552-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/fad58a79ef17/fimmu-09-01552-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/e46c51a0a098/fimmu-09-01552-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/1a719c52243f/fimmu-09-01552-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/2e89b21db294/fimmu-09-01552-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/8f66452af2f3/fimmu-09-01552-g005a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/1e7ba52b9bc9/fimmu-09-01552-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/989f9fd25bfd/fimmu-09-01552-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/30aff605c2c3/fimmu-09-01552-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/fad58a79ef17/fimmu-09-01552-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/e46c51a0a098/fimmu-09-01552-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/1a719c52243f/fimmu-09-01552-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/2e89b21db294/fimmu-09-01552-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/8f66452af2f3/fimmu-09-01552-g005a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/1e7ba52b9bc9/fimmu-09-01552-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/989f9fd25bfd/fimmu-09-01552-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9199/6043652/30aff605c2c3/fimmu-09-01552-g008.jpg

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