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

Rothe, Tobias, Gruber, Florian, Uderhardt, Stefan, Ipseiz, Natacha ORCID: https://orcid.org/0000-0001-5008-8889, 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:	10 Jun 2023 01:45
URI:	https://orca.cardiff.ac.uk/id/eprint/127552

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