Loss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in arthritis

Yilin Wang, Aneesah Khan, Aristotelis Antonopoulos, Laura Bouché, Christopher D. Buckley, Andrew Filer, Karim Raza, Kun-Ping Li, Barbara Tolusso, Elisa Gremese, Mariola Kurowska-Stolarska, Stefano Alivernini, Anne Dell, Stuart M. Haslam and Miguel A. Pineda ()
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Yilin Wang: University of Glasgow
Aneesah Khan: University of Glasgow
Aristotelis Antonopoulos: Department of Life Sciences, Imperial College London
Laura Bouché: Department of Life Sciences, Imperial College London
Christopher D. Buckley: University of Birmingham, Queen Elizabeth Hospital
Andrew Filer: University of Birmingham, Queen Elizabeth Hospital
Karim Raza: University of Birmingham, Queen Elizabeth Hospital
Kun-Ping Li: Guangdong Pharmaceutical University
Barbara Tolusso: Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, Birmingham
Elisa Gremese: Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, Birmingham
Mariola Kurowska-Stolarska: University of Glasgow
Stefano Alivernini: Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, Birmingham
Anne Dell: Department of Life Sciences, Imperial College London
Stuart M. Haslam: Department of Life Sciences, Imperial College London
Miguel A. Pineda: University of Glasgow

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract In healthy joints, synovial fibroblasts (SFs) provide the microenvironment required to mediate homeostasis, but these cells adopt a pathological function in rheumatoid arthritis (RA). Carbohydrates (glycans) on cell surfaces are fundamental regulators of the interactions between stromal and immune cells, but little is known about the role of the SF glycome in joint inflammation. Here we study stromal guided pathophysiology by mapping SFs glycosylation pathways. Combining transcriptomic and glycomic analysis, we show that transformation of fibroblasts into pro-inflammatory cells is associated with glycan remodeling, a process that involves TNF-dependent inhibition of the glycosyltransferase ST6Gal1 and α2-6 sialylation. SF sialylation correlates with distinct functional subsets in murine experimental arthritis and remission stages in human RA. We propose that pro-inflammatory cytokines remodel the SF-glycome, converting the synovium into an under-sialylated and highly pro-inflammatory microenvironment. These results highlight the importance of glycosylation in stromal immunology and joint inflammation.

Date: 2021
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DOI: 10.1038/s41467-021-22365-z

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