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A Microbial Polysaccharide Reduces the Severity of Rheumatoid Arthritis by Influencing Th17 Differentiation and Proinflammatory Cytokines Production¹

Claudia Monari^*, Sara Bevilacqua^*, Miranda Piccioni^*, Eva Pericolini^*, Stefano Perito^*, Mario Calvitti, Francesco Bistoni^*, Thomas R. Kozel and Anna Vecchiarelli^2,*

^* Department of Experimental Medicine and Biochemical Sciences, Microbiology Section, and Department of Experimental Medicine and Biochemical Sciences, Histological Section, University of Perugia, Perugia, Italy; and Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV 89557

Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease characterized by chronic joint inflammation with subsequent cartilage and bone destruction. RA is emerging as a model of IL-17-driven autoimmune inflammatory disease. IL-17 is a marker for Th17 cells, with its master regulator being the retinoic acid receptor-related orphan receptor (RORt) regulated by STAT3 signaling. Glucuronoxylomannan (GXM), a polysaccharide representing the main component of the capsular material of the opportunistic yeast Cryptococcus neoformans, exhibits potent immunosuppressive properties both in vitro and in vivo. The present study investigates the effects of GXM treatment on the progression of collagen-induced arthritis. GXM suppressed clinical signs of collagen-induced arthritis and blocked joint erosion progression. This effect was mediated by down-regulation of key cytokines involved in the pathogenesis of RA such as TNF- and IL-1β, and up-regulation of the inhibitory cytokine IL-10. Moreover, a reduction of IL-6 and TGF-β, which inhibit Th17 differentiation with consequent decreased IL-17 production at the local and systemic level, was observed. The effect of GXM on Th17 differentiation mirrored the reduction in STAT3 activation and inhibition of RORt synthesis. Consequently, this work highlights the beneficial properties of an efficacious compound that could eventually be destined to the clinic.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Funds of Investment for Basic Research, protocol no. RBLA03C9F4_006.

² Address correspondence and reprint requests to Prof. Anna Vecchiarelli, Department of Experimental Medicine and Biochemical Sciences, Microbiology Section, University of Perugia, Via del Giochetto, 06122 Perugia, Italy. E-mail address: vecchiar{at}unipg.it

³ Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen type II (CII)-induced arthritis; GXM, glucuronoxylomannan; Dex, dexamethasone; RORt, retinoic acid receptor-related orphan receptor.

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