Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis  

作　　者：Anja Meyer Stephanie R.Zack Wes Nijim Adel Burgos Vishwa Patel Brian Zanotti Michael V.Volin M.Asif Amin Myles J.Lewis Costantino Pitzalis Shiva Arami Joseph A.Karam Nadera J.Sweiss Shiva Shahrara 

机构地区：[1]Jesse Brown VA Medical Center,Chicago,IL,USA [2]Department of Medicine,Division of Rheumatology,The University of Illinois at Chicago,Chicago,IL,USA [3]Department of Microbiology and Immunology,Midwestern University,Downers Grove,IL,USA [4]Division of Rheumatology and Clinical Autoimmunity Center of Excellence,University of Michigan,Ann Arbor,MI,USA [5]Centre for Experimental Medicine and Rheumatology,William Harvey Research Institute,Barts and The London School of Medicine and Dentistry,Queen Mary University of London,London,United Kingdom [6]Centre for Experimental Medicine&Rheumatology,William Harvey Research Institute,Queen Mary University of London and Barts NIHR BRC&NHS Trust,London,UK [7]Department of Biomedical Sciences,Humanitas University,and Humanitas Research Hospital,Milan,Italy [8]Department of Orthopedic Surgery,the University of Illinois at Chicago,Chicago,IL,USA

出　　处：《Cellular & Molecular Immunology》2024年第1期33-46,共14页中国免疫学杂志（英文版）

基　　金：supported in part by awards from the Department of Veteran’s Affairs MERIT Award BX002286,CX002565,IK6BX006474;the National Institutes of Health NIH R01 AI167155,NIH R41 AI147697;the Innovative Research Award from the Rheumatology Research Foundation(RRF,no number assigned).

摘　　要：A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9,IL-1β,IL-6,and CCL2 through SDC-1 ligation and HIF1α,or mTOR activation.Mechanistically,Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling.In Syntenin-1 reprogrammed endothelial cells,the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors,AMPK,PGC-1α,citrate,and inactive oxidative phosphorylation.Conversely,RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity.The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression.We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS,which are also represented in RA explants.Similar to RA explants,morphological and transcriptome studies authenticated the importance of VEGFR1/2,Notch1,RAPTOR,and HIF1αpathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals.Consistently,dysregulation of SDC-1,mTOR,and HIF1αnegated Syntenin-1 inflammatory phenotype in RA explants,while inhibition of HIF1αimpaired synovial angiogenic imprint amplified by Syntenin-1.In conclusion,since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood,targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.

关 键 词：Syntenin-1 SYNDECAN-1 RA FLS RA explants immunometabolism 

分 类 号：R392[医药卫生—免疫学]