Long-chain acyl-CoA synthetase 4-mediated mitochondrial fatty acid metabolism and dendritic cell antigen presentation
作者全名："Li, Yan; Fu, Wenlong; Xiang, Jinying; Ren, Yinying; Li, Yuehan; Zhou, Mi; Yu, Jinyue; Luo, Zhengxiu; Liu, Enmei; Fu, Zhou; Liu, Bo; Ding, Fengxia"
作者地址："[Li, Yan; Fu, Wenlong; Xiang, Jinying; Ren, Yinying; Li, Yuehan; Zhou, Mi; Luo, Zhengxiu; Liu, Enmei; Fu, Zhou; Ding, Fengxia] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Dept Resp Med,Childrens Hosp,Minist Educ,China Int, 136 Zhongshan 2 Rd, Chongqing 400014, Peoples R China; [Liu, Bo] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, China Int Sci & Technol Cooperat Base Child Dev &, Dept Cardiothorac Surg,Childrens Hosp,Minist Educ,, 136 Zhongshan 2 Rd, Chongqing 400014, Peoples R China; [Li, Yan; Fu, Wenlong; Xiang, Jinying; Ren, Yinying; Li, Yuehan; Zhou, Mi; Luo, Zhengxiu; Liu, Enmei; Fu, Zhou; Liu, Bo; Ding, Fengxia] Chongqing Med Univ, Chongqing Engn Res Ctr Stem Cell Therapy, Chongqing Key Lab Pediat, Chongqing, Peoples R China; [Yu, Jinyue] Univ Bristol, Bristol Med Sch, Bristol, England; [Yu, Jinyue] UCL, Great Ormond St Inst Child Hlth, London, England"
通信作者："Ding, FX (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Dept Resp Med,Childrens Hosp,Minist Educ,China Int, 136 Zhongshan 2 Rd, Chongqing 400014, Peoples R China.; Liu, B (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, China Int Sci & Technol Cooperat Base Child Dev &, Dept Cardiothorac Surg,Childrens Hosp,Minist Educ,, 136 Zhongshan 2 Rd, Chongqing 400014, Peoples R China.; Liu, B; Ding, FX (通讯作者)，Chongqing Med Univ, Chongqing Engn Res Ctr Stem Cell Therapy, Chongqing Key Lab Pediat, Chongqing, Peoples R China."
来源：INFLAMMATION RESEARCH
ESI学科分类：IMMUNOLOGY
WOS号：WOS:001181192400001
JCR分区：Q2
影响因子：4.8
年份：2024
卷号：
期号：
开始页：
结束页：
文献类型：Article; Early Access
关键词：Asthma; Acyl-CoA synthetase 4; Dendritic cells; Mitochondria
摘要："ObjectiveThis study aims to investigate the role of Acyl-CoA synthetase 4 (ACSL4) in mediating mitochondrial fatty acid metabolism and dendritic cell (DC) antigen presentation in the immune response associated with asthma.MethodsRNA sequencing was employed to identify key genes associated with mitochondrial function and fatty acid metabolism in DCs. ELISA was employed to assess the levels of fatty acid metabolism in DCs. Mitochondrial morphology was evaluated using laser confocal microscopy, structured illumination microscopy, and transmission electron microscopy. Flow cytometry and immunofluorescence were utilized to detect changes in mitochondrial superoxide generation in DCs, followed by immunofluorescence co-localization analysis of ACSL4 and the mitochondrial marker protein COXIV. Subsequently, pathological changes and immune responses in mouse lung tissue were observed. ELISA was conducted to measure the levels of fatty acid metabolism in lung tissue DCs. qRT-PCR and western blotting were employed to respectively assess the expression levels of mitochondrial-associated genes (ATP5F1A, VDAC1, COXIV, TFAM, iNOS) and proteins (ATP5F1A, VDAC1, COXIV, TOMM20, iNOS) in lung tissue DCs. Flow cytometry was utilized to analyze changes in the expression of surface antigens presented by DCs in lung tissue, specifically the MHCII molecule and the co-stimulatory molecules CD80/86.ResultsThe sequencing results reveal that ACSL4 is a crucial gene regulating mitochondrial function and fatty acid metabolism in DCs. Inhibiting ACSL4 reduces the levels of fatty acid oxidases in DCs, increases arachidonic acid levels, and decreases A-CoA synthesis. Simultaneously, ACSL4 inhibition leads to an increase in mitochondrial superoxide production (MitoSOX) in DCs, causing mitochondrial rupture, vacuolization, and sparse mitochondrial cristae. In mice, ACSL4 inhibition exacerbates pulmonary pathological changes and immune responses, reducing the fatty acid metabolism levels within lung tissue DCs and the expression of mitochondria-associated genes and proteins. This inhibition induces an increase in the expression of MHCII antigen presentation molecules and co-stimulatory molecules CD80/86 in DCs.ConclusionsThe research findings indicate that ACSL4-mediated mitochondrial fatty acid metabolism and dendritic cell antigen presentation play a crucial regulatory role in the immune response of asthma. This discovery holds promise for enhancing our understanding of the mechanisms underlying asthma pathogenesis and potentially identifying novel targets for its prevention and treatment."
基金机构："Graduate Student Research and Innovation Project of Chongqing Municipality; Scientific Natural Science Foundation of Chongqing [cstc2020jcyj-msxmX0615]; Youth Project of Scientific and Technological Research of Chongqing Municipal Education Commission [KJQN202200411, 2023QNXM015]; China Postdoctoral Science Foundation [2021MD703923]"
基金资助正文："This study was supported by the Scientific Natural Science Foundation of Chongqing (cstc2020jcyj-msxmX0615), Youth Project of Scientific and Technological Research of Chongqing Municipal Education Commission (KJQN202200411), Chongqing Municipal Health Commission-Joint Scientific Research Project (2023QNXM015) and China Postdoctoral Science Foundation (2021MD703923) and the Graduate Student Research and Innovation Project of Chongqing Municipality (No.CYB22211)."
