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-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 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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All data generated or analyzed during this study are included in this paper and its supplementary information files.
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Acknowledgements
The authors would like to thank Dr. Sadiq Umar for assistance with RA FLS culture and Ms. Pei-Yu Wu for her excellent scientific advice, and the Fluorescent Immunohistochemistry Midwestern University Core Facility, Downers Grove, IL for analyzing the fluorescent stainings. Moreover, we would like to acknowledge Dr. Caroline Alexander (University of Wisconsin–Madison) for generously providing us with SDC-1-/- mice [30]. Schematic figures were illustrated by biorender.com.
Funding
This work was 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, and the Innovative Research Award from the Rheumatology Research Foundation (RRF, no number assigned).
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All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Shahrara had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: AM, SZ, SS Acquisition of data: AM, SZ, WN, AB, VP, BZ, MV, ML, CP, SS Analysis and interpretation of data: AM, SZ, WN, AB, VP, BZ, MV, MAA, ML, CP, IM, SA, JAK, NS, SS Providing crucial reagents: MAA, SA, JAK, NS.
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RA patients were collected according to the protocol approved by the University of Illinois at Chicago Institutional Ethics Review Board (protocol# 2021-1494). All animal studies were approved by the University of Illinois at Chicago Animal Care and Use Committee (protocol# 22-008). To ensure a robust and unbiased experimental design, samples were obtained from RA patients or mice of both genders. Mice used within the same experimental group were age and sex-matched. Rigor and reproducibility were maintained through well-powered studies and multiple distinct approaches to confirm the results. Power was calculated using parameters of α=0.05, and power=90%.
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The authors declare no competing interests.
Supplementary information
41423_2023_1108_MOESM1_ESM.tif
Supplementary figure 1. Blood Syntenin-1 and SDC-1 relative levels are unaffected by RA therapy and glycolytic metabolites can modulate inflammatory factors and oxidative metabolites in Syntenin-1 rep
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Supplementary figure 3. GLUT1 is co-expressed on Vimentin+fibroblasts and VWF+endothelial cells in Syntenin-1 arthritic joints
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Supplementary figure 4. HK2 is co-expressed on Vimentin+fibroblasts and VWF+endothelial cells in Syntenin-1 arthritic joints
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Meyer, A., Zack, S.R., Nijim, W. et al. Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis. Cell Mol Immunol 21, 33–46 (2024). https://doi.org/10.1038/s41423-023-01108-8
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DOI: https://doi.org/10.1038/s41423-023-01108-8
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