期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 125, 期 5, 页码 1944-1954出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI78490
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资金
- Else-Kroner Fresenius Stiftung
- Deutsche Forschungsgemeinschaft [SCHE1583, KR3523, FG 661, SFB 643, SPP1468-IMMUNOBONE]
- ELAN-Program of the University of Erlangen-Nuremberg
- MASTERSWITCH project of the European Union
- Interdisciplinary Centre for Clinical Research, Erlangen
- Fonds zur Forderung wissenschaftlicher Forschung [P22267-B11]
- NIH [R01 DK096076]
- Austrian Science Fund (FWF) [P22267] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [P 22267] Funding Source: researchfish
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.
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