12/15-lipoxygenase–mediated enzymatic lipid oxidation regulates DC maturation and function
Tobias Rothe, Florian Gruber, Stefan Uderhardt, Natacha Ipseiz, Susanne Rössner, Olga Oskolkova, Stephan Blüml, Norbert Leitinger, Wolfgang Bicker, Valery N. Bochkov, Masayuki Yamamoto, Alexander Steinkasserer, Georg Schett, Elisabeth Zinser, Gerhard Krönke
Tobias Rothe, Florian Gruber, Stefan Uderhardt, Natacha Ipseiz, Susanne Rössner, Olga Oskolkova, Stephan Blüml, Norbert Leitinger, Wolfgang Bicker, Valery N. Bochkov, Masayuki Yamamoto, Alexander Steinkasserer, Georg Schett, Elisabeth Zinser, Gerhard Krönke
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Research Article Immunology

12/15-lipoxygenase–mediated enzymatic lipid oxidation regulates DC maturation and function

Abstract

DCs are able to undergo rapid maturation, which subsequently allows them to initiate and orchestrate T cell–driven immune responses. DC maturation must be tightly controlled in order to avoid random T cell activation and development of autoimmunity. Here, we determined that 12/15-lipoxygenase–meditated (12/15-LO–mediated) enzymatic lipid oxidation regulates DC activation and fine-tunes consecutive T cell responses. Specifically, 12/15-LO activity determined the DC activation threshold via generation of phospholipid oxidation products that induced an antioxidative response dependent on the transcription factor NRF2. Deletion of the 12/15-LO–encoding gene or pharmacologic inhibition of 12/15-LO in murine or human DCs accelerated maturation and shifted the cytokine profile, thereby favoring the differentiation of Th17 cells. Exposure of 12/15-LO–deficient DCs to 12/15-LO–derived oxidized phospholipids attenuated both DC activation and the development of Th17 cells. Analysis of lymphatic tissues from 12/15-LO–deficient mice confirmed enhanced maturation of DCs as well as an increased differentiation of Th17 cells. Moreover, experimental autoimmune encephalomyelitis in mice lacking 12/15-LO resulted in an exacerbated Th17-driven autoimmune disease. Together, our data reveal that 12/15-LO controls maturation of DCs and implicate enzymatic lipid oxidation in shaping the adaptive immune response.

Authors

Tobias Rothe, Florian Gruber, Stefan Uderhardt, Natacha Ipseiz, Susanne Rössner, Olga Oskolkova, Stephan Blüml, Norbert Leitinger, Wolfgang Bicker, Valery N. Bochkov, Masayuki Yamamoto, Alexander Steinkasserer, Georg Schett, Elisabeth Zinser, Gerhard Krönke

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Figure 1

BM-DCs express functionally active 12/15-LO.

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BM-DCs express functionally active 12/15-LO. (A) Quantification of Alox1...
(A) Quantification of Alox15 mRNA expression levels in immature BM-DCs from WT and Alox15–/– mice or of Alox15 mRNA expression in WT BM-DCs after stimulation with LPS (100 ng/ml) for indicated intervals. Error bars represent SEM. (B) Western blot analysis of 12/15-LO protein levels in extracts of BM-DCs and peritoneal macrophages (MΦ) isolated from WT and Alox15–/– mice and WT or Alox15–/– BM-DCs after maturation with LPS (100 ng/ml for 24 hours). (C) Determination of different 12/15-LO–derived oxidation products in WT and Alox15–/– BM-DCs, as quantified by mass spectrometry. Peak area was normalized to an internal standard (1,2-dinonanoyl-sn-glycero-3-phosphocholine [DNPC]). Data shown are representative of 3 independent experiments (n = 3).