Enhanced Th17 Differentiation and Aggravated Arthritis in IEX-1–Deficient Mice by Mitochondrial Reactive Oxygen Species-Mediated Signaling
| Autor: | Mei X. Wu, Liang Zhi, Qi Zhang, Irina V. Ustyugova, Xinyuan Chen |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 189:1639-1647 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | CD4+ Th1 and Th17 cells both can cause autoimmune diseases, either alone or collaboratively, if left unchecked. However, what determines the dominant Th effector phenotype in a specific autoimmune disease remains poorly understood. Our present investigation shows that null mutation of IEX-1 promotes differentiation of Th17 cells but compromises the survival of Th1 cells. The differential effect gave rise to a greater number of Th17 cells, a higher level of IL-17 production, and more severe arthritis in IEX-1 knockout mice than in wild-type mice after immunizations with collagen. IEX-1 deficiency-facilitated Th17 cell differentiation was mediated by the increased formation of reactive oxygen species (ROS) at mitochondria following T cell activation, as suggested by marked inhibition of Th17 induction with ROS scavenger N-acetylcysteine or mitoquinone, a specific inhibitor for mitochondrial ROS production. Mitochondrial ROS augmented the expression of B cell-activating transcription factor, which may contribute to increased IL-17 production in the absence of IEX-1, in light of its importance in IL-17 transcription. The results demonstrate that mitochondrial ROS contribute significantly to the dominant Th effector phenotype in autoimmunity in addition to the cytokine milieu. |
| Databáze: | OpenAIRE |
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