Enhanced Th17 differentiation and aggravated arthritis in IEX-1-deficient mice by mitochondrial reactive oxygen species-mediated signaling.
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.
Department of Dermatology, Wellman Center for Photomedicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA.
Liang
L
Zhi
Irina V
IV
Ustyugova
Xinyuan
X
Chen
Qi
Q
Zhang
Mei X
MX
Wu
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002470:Cell Survival; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology; D014162:Transfection
C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D017382:Reactive Oxygen Species