Synovial Fibroblast Sialylation Regulates Cell Migration and Activation of Inflammatory Pathways in Arthritogenesis

Abstract

Synovial fibroblasts have emerged as critical underlying factors to perpetuate chronic joint inflammation in Rheumatoid Arthritis. Like any other cell, synovial fibroblasts are covered with a complex layer of glycans that can change in response to extracellular signals, such as inflammation. We have previously shown that inflammatory synovial fibroblasts show decreased levels of sialic acid, but our understanding of sialic acid-dependent pathophysiological pathways in these stromal cells is still very limited. In this report, we used in vivo and in vitro studies with exogenous sialidases and RNA sequencing to investigate the responses of murine synovial fibroblasts upon desialylation. Our results show that hyposialylated fibroblasts present a dysregulated migratory ability and an activated phenotype characterized by the expression of inflammatory mediators, such as cytokines and chemokines, and anti-viral related mechanisms. Removal of surface sialic acid also affected the expression of sialyltransferases, revealing the existence of a positive feedback to sustain reduced sialylation. Moreover, we demonstrate that synovial fibroblasts subsets have distinct sialyltransferase expression profiles, both in healthy and arthritic mice. These findings underline the ability of sialic acid to modulate homeostatic and inflammatory responses in non-immune synovial fibroblasts, suggesting that sialylation plays a key role in perpetuating local inflammation in the arthritic joint.

EPO promotes the progression of rheumatoid arthritis by inducing desialylation via increasing the expression of neuraminidase 3

“…Studies reported the decreased sialylation in RA FLS, which promotes its invasion ability 24 25. NEU3, an enzyme of desialylation,26 might be involved in the desialylation of RA FLS.…”

“…Studies have shown that the sialylation level was decreased in RA, and the desialylation of ACPA exacerbated the development of RA 20 21. In addition, the decreased sialylation level of FLS promotes its migration and invasion, leading to the transition to a pathogenic state 24 25. Sialylation is regulated by sialyltransferase and neuraminidase (NEU), mediating the reaction of sialylation and desialylation, respectively.…”

“…In addition, our previous studies also confirmed that the decreased β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) was an important cause of ACPA desialylated in patients with RA 23. In vivo studies showed that sialylated ACPA reduced the arthritis score of CIA mice,20 and the decreased sialylation of FLS enhanced the inflammatory condition of microenvironment in synovial tissue 24 25…”

Inflammatory Synovial Fibroblast Culture in 3D Systems: A Comparative Transcriptomic and Functional Study

“…This confirmed SF activation, dominated by enriched functional nodes containing cytokine signalling (IL-17 and TNF), JAK-STAT signalling and cell cycle activation (Figure 2D), in line with the expected arthritic phenotype. To further illustrate this, we designed four gene lists to provide a tailored analysis of mechanisms of known importance for SF-mediated immunopathology which will be relevant for comparison with ex vivo 2D and 3D cultures: i) proliferation, ii) matrix remodeling, iii) secretion of inflammatory mediators and iv) migratory response (37, 43, 44) (Figure 2E). As expected, all selected genes were up-regulated in activated CIA SFs.…”