Ppar & alpha; knockout in mice increases the Th17 development by facilitating the IKK & alpha;/ROR & gamma;t and IKK & alpha;/Foxp3 complexes

作者全名："Wei, Ping; Kou, Wei; Fu, Juan; Chen, Zuojia; Pan, Fan"

作者地址："[Wei, Ping; Kou, Wei] Chongqing Med Univ, Childrens Hosp, China Int Sci & Technol Cooperat base Child Dev &, Dept Otolaryngol,Minist Educ,Key Lab Child Dev & D, Chongqing, Peoples R China; [Kou, Wei; Pan, Fan] Chinese Acad Sci, Shenzhen Inst Adv Technol SIAT, 1068 Xueyuan Ave, Shenzhen 518055, Peoples R China; [Fu, Juan; Pan, Fan] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Dept Oncol, Baltimore, MD 21218 USA; [Chen, Zuojia] NCI, NIH, Expt Immunol Branch, Bethesda, MD USA"

通信作者："Pan, F (通讯作者)，Chinese Acad Sci, Shenzhen Inst Adv Technol SIAT, 1068 Xueyuan Ave, Shenzhen 518055, Peoples R China.; Pan, F (通讯作者)，Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Dept Oncol, Baltimore, MD 21218 USA."

来源：COMMUNICATIONS BIOLOGY

ESI学科分类：　

WOS号：WOS:001028812100005

JCR分区：Q1

影响因子：5.2

年份：2023

卷号：6

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："The helper CD4(+) T cell-type 17 (Th17) cells and regulatory CD4(+) T cells (Tregs) are balanced through numerous molecular regulators, particularly metabolic factors, and their alteration causes immune dysregulation. Herein, we report that peroxisome proliferator of activated receptor-alpha (Ppar & alpha;), a lipid metabolism regulator, suppresses Th17 differentiation. We demonstrated that Ppar & alpha; ablation improves Th17 and pro-Th17 factor HIF-1 & alpha; by enhancing the expression and nuclear localization of NF & kappa;B-activator I & kappa;B kinase-alpha (IKK & alpha;). Unexpectedly, we found that IKK & alpha; directly interacts with ROR & gamma;t and enhances the expression of Il17a gene. Meanwhile, IKK & alpha; also interacts with Foxp3, leading to the post-translational regulation of Foxp3 by elevating its proteasomal degradation, and influencing Th17 development. Ppar & alpha; deficiency leads to enhanced Th17 development in vivo and is associated with enhanced pathology in a murine experimental autoimmune encephalomyelitis (EAE) model. Overall, our data indicate that Ppar & alpha; may serve as a potential therapeutic target for autoimmune and inflammatory diseases. Upregulation of Ppar & alpha; in activated CD4(+) T cells inhibits IKK & alpha; expression and IKK & alpha;dependent degradation of Foxp3 and elevation of IL17a, thus could constitute a potential therapeutic target for autoimmune, cancer and inflammatory diseases"

基金机构："National Key Ramp;D Program of China [2021YFC2400500]; National Natural Science Foundation of China [32170925]; Shenzhen Science and Technology Program [JCYJ2022081800807016, CX2022118]; Natural Science Foundation of Chongqing [CSTB2022NSCQ-MSX1069]; startup fund of SIAT; CAS; Entrepreneurship and Innovation Support Program of Chongqing for overseas Scholars; [KQTD20210811090115019]"

基金资助正文："This work was supported by the National Key R & amp;D Program of China (2021YFC2400500), the National Natural Science Foundation of China (Grant 32170925), Shenzhen Science and Technology Program (KQTD20210811090115019), the Shenzhen Science and Technology Program (JCYJ2022081800807016), the startup fund of SIAT and CAS, the Natural Science Foundation of Chongqing Grant CSTB2022NSCQ-MSX1069, the Entrepreneurship and Innovation Support Program of Chongqing for overseas Scholars Grant CX2022118. The authors declare no competing financial interests."