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

Frontiers in Immunology

Christoph Wruck¹  Athanassios Fragoulis²  Julia Möllmann³  Michael Lehrke³  Klaus Tenbrock⁴  Patricia Klemm⁴  Wiebke Klock⁴  Angela Schippers⁴  Norbert Wagner⁴  Kim Ohl⁴  Julian Baumeister⁴  Johannes Roth⁵  Svenja Böll⁶  Eva Verjans⁶  Bernd Denecke⁷  Ivan Costa⁷ 

[1] Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen, Aachen, Germany;Department of General Visceral and Transplantation Surgery, Molecular Tumor Biology, Medical Faculty, RWTH Aachen, Aachen, Germany;Department of Medicine I, Medical Faculty, RWTH Aachen, Aachen, Germany;Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany;Institute of Immunology, University of Münster, Münster, Germany;Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany;Interdisciplinary Centre for Clinical Research (IZKF) Aachen, Medical Faculty, RWTH Aachen, Aachen, Germany;

关键词: Nrf2;    myeloid-derived suppressor cell;    LPS;    sepsis;    ROS;   

DOI  :  10.3389/fimmu.2018.01552

来源: DOAJ

【 摘 要 】

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 CD11b+Gr-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 CD11b+Gr-1+ MDSCs expanded by in vivo 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.

【 授权许可】

Unknown