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

Wang, Y. et al. (2021) Loss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in arthritis. Nature Communications, 12, 2343. (doi: 10.1038/s41467-021-22365-z) (PMID:33879788) (PMCID:PMC8058094)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Khan, Aneesah and Wang, Yilin and Filer, Dr Andrew and Buckley, Professor Christopher and Kurowska-Stolarska, Dr Mariola and Pineda, Dr Miguel and Alivernini, Mr Stefano
Authors: Wang, Y., Khan, A., Antonopoulos, A., Bouché, L., Buckley, C. D., Filer, A., Raza, K., Ping-Li, K., Tolusso, B., Gremese, E., Kurowska-Stolarska, M., Alivernini, S., Dell, A., Haslam, S. M., and Pineda, M. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Nature Communications
Publisher:Nature Research
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Nature Communications 12:2343
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172504Harnessing glycan-dependent pathways in synovial fibroblasts to control chronic joint inflammation?Miguel PinedaVersus Arthritis (ARTRESUK)21221III - Immunology