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

Rothe, Tobias, Gruber, Florian, Uderhardt, Stefan, Ipseiz, Natacha, Rössner, Susanne, Oskolkova, Olga, Blüml, Stephan, Leitinger, Norbert, Bicker, Wolfgang, Bochkov, Valery N., Yamamoto, Masayuki, Steinkasserer, Alexander, Schett, Georg, Zinser, Elisabeth and Krönke, Gerhard 2015. 12/15-lipoxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function. The Journal of Clinical Investigation 125 (5) , pp. 1944-1954. 10.1172/JCI78490

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Date of Acceptance: 27 February 2015
Last Modified: 19 Dec 2019 17:49
URI: http://orca-mwe.cf.ac.uk/id/eprint/127552

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