title: 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.forename: Tobias
authors.initials: T
authors.lastname: Rothe
authors.forename: Florian
authors.initials: F
authors.lastname: Gruber
authors.forename: Stefan
authors.initials: S
authors.lastname: Uderhardt
authors.forename: Natacha
authors.initials: N
authors.lastname: Ipseiz
authors.forename: Susanne
authors.initials: S
authors.lastname: Rössner
authors.forename: Olga
authors.initials: O
authors.lastname: Oskolkova
authors.forename: Stephan
authors.initials: S
authors.lastname: Blüml
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bicker
authors.forename: Valery N
authors.initials: VN
authors.lastname: Bochkov
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinkasserer
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Zinser
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D008221:Lymphoid Tissue / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology
chemical_list: D005227:Fatty Acids; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010743:Phospholipids; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
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