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Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis.
Meyer, Anja; Zack, Stephanie R; Nijim, Wes; Burgos, Adel; Patel, Vishwa; Zanotti, Brian; Volin, Michael V; Amin, M Asif; Lewis, Myles J; Pitzalis, Costantino; Arami, Shiva; Karam, Joseph A; Sweiss, Nadera J; Shahrara, Shiva.
Afiliación
  • Meyer A; Jesse Brown VA Medical Center, Chicago, IL, USA.
  • Zack SR; Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, Chicago, IL, USA.
  • Nijim W; Jesse Brown VA Medical Center, Chicago, IL, USA.
  • Burgos A; Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, Chicago, IL, USA.
  • Patel V; Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, Chicago, IL, USA.
  • Zanotti B; Jesse Brown VA Medical Center, Chicago, IL, USA.
  • Volin MV; Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, Chicago, IL, USA.
  • Amin MA; Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, Chicago, IL, USA.
  • Lewis MJ; Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL, USA.
  • Pitzalis C; Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL, USA.
  • Arami S; Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, USA.
  • Karam JA; 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.
  • Sweiss NJ; Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Queen Mary University of London and Barts NIHR BRC & NHS Trust, London, UK.
  • Shahrara S; 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.
Cell Mol Immunol ; 21(1): 33-46, 2024 01.
Article en En | MEDLINE | ID: mdl-38105293
ABSTRACT
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-1ß, 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 HIF1α pathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals. Consistently, dysregulation of SDC-1, mTOR, and HIF1α negated Syntenin-1 inflammatory phenotype in RA explants, while inhibition of HIF1α impaired 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Artritis Reumatoide / Sinoviocitos Límite: Animals Idioma: En Revista: Cell Mol Immunol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: China
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Artritis Reumatoide / Sinoviocitos Límite: Animals Idioma: En Revista: Cell Mol Immunol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: China