The Microbial Capsular Polysaccharide Galactoxylomannan Inhibits IL-17A Production in Circulating T Cells from Rheumatoid Arthritis Patients

Eva Pericolini,Arturo Casadevall,Anna Vecchiarelli,Giovanni Bistoni,Roberto Gerli,Alessia Alunno,Elena Bartoloni,Siu-Kei Chow,Elena Gabrielli,Elio Cenci

doi:10.1371/journal.pone.0053336

Eva Pericolini, Arturo Casadevall + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0053336

Copy DOI

Abstract

The persistence of activated T cells in rheumatoid arthritis (RA) synovium may be attributable to increased homing, increased retention or a possible imbalance between cell proliferation and programmed cell death. Induction of apoptosis may represent a potential therapeutic approach. Galactoxylomannan (GalXM) from the opportunistic fungus Cryptococcus neoformans can interact with T cells and induce T-cell apoptosis through the inhibition of CD45 phosphatase activity. The aim of this study was to determine the effect of GalXM on circulating T cells from patients with RA and the underlying mechanisms. GalXM immunomodulating effect on apoptosis and signal transduction pathway involved in IL-17A production was evaluated on T cells. RA T-cell apoptosis, higher than that of control T cells, was further increased by GalXM through induction of caspase-3 activation. Activated T cells expressing the CD45RO molecule and producing IL-17A were the main target of GalXM-induced apoptosis. GalXM induced consistent impairment of IL-17A production and inhibition of STAT3, which was hyperactivated in RA. In conclusion, GalXM triggered apoptosis of activated memory T cells and interfered with IL-17A production in RA. These data suggest therapeutic targeting of deleterious Th17 cells in RA and other autoimmune diseases.

Highlights

Rheumatoid arthritis (RA) is a chronic autoimmune and inflammatory systemic disease that primarily affects synovial joints
We evaluated the effect of GalXM on the apoptosis of cells from synovial fluid of osteoarthritis (OA) and RA patients after 18 h of treatment
The abundance of activated CD4+ T cells in the synovium of individuals with RA, especially people who express certain allelic forms of the MHC II b-chain (e.g., HLA-DRB1*0401), indicates that the process of antigen recognition by CD4+ cells plays a critical role in the pathogenesis of RA [1]

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune and inflammatory systemic disease that primarily affects synovial joints. In RA, Fas and FasL have been detected in synovial cells, which are susceptible to Fas-mediated apoptosis induced by an anti-Fas mAb [13]. The inflammatory milieu of the rheumatoid cells is likely to contribute to the degree of Fas-mediated apoptosis, since proinflammatory cytokines such as TNF-a and IL-1b suppress apoptosis in vitro [13,14]. In this context, the possibility to selectively eliminate RA pathogenic synovial T cells by targeted activation of Fas-apoptotic signaling may be of value as novel therapeutic approach [15]. IL-17A induces production of pro-inflammatory mediators such as TNF-

Objectives

Methods

Results

Conclusion