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

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

doi:10.4049/jimmunol.0804144

Cited by 39 publications

(34 citation statements)

References 49 publications

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“…Thus, the inhibitory effect of GXM can occur regardless of LPS activation. Consistent with this hypothesis is the anti-inflammatory effect of GXM we previously reported for an experimental model of rheumatoid arthritis (34).…”

Section: Discussionsupporting

confidence: 75%

“…The dose of GXM (100 g/mouse) was extrapolated from previous in vivo experiments which demonstrated that this was the appropriate dose to inhibit proinflammatory cytokine secretion and to positively influence septic arthritis and rheumatoid arthritis, pathologies characterized by aberrant inflammatory responses (33,34). A lower dose of GXM (10 g/mouse) was also used, but under this experimental condition, GXM did not affect the course of LPS-induced sepsis.…”

Section: Gxm Improves Survival Of Endotoxemic Micementioning

confidence: 99%

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A Purified Capsular Polysaccharide Markedly Inhibits Inflammatory Response during Endotoxic Shock

et al. 2013

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b Capsular material of the opportunistic fungus Cryptococcus neoformans is composed mainly of a polysaccharide named glucuronoxylomannan (GXM). In this study, the effects of GXM were analyzed in an in vivo experimental system of lipopolysaccharide (LPS)-induced shock. Endotoxic shock was induced in mice by a single intraperitoneal injection of LPS from Escherichia coli. GXM treatment reduced the mortality of mice at early stages. Mice treated with LPS alone showed markedly increased plasma levels of tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), and IL-6, whereas mice that were also treated with GXM showed significantly lower plasma levels of these cytokines. This effect was related to a marked suppression of Akt and IB␣ activation. Importantly, the inhibitory effect of GXM on proinflammatory cytokine secretion was reproduced by treatment with wortmannin, an inhibitor of the Akt transcription pathway. Our results indicate that GXM has a beneficial effect on endotoxic shock, resulting in a significant increase in the rate of survival by dampening the hyperinflammatory response.

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Section: Discussionsupporting

confidence: 75%

Section: Gxm Improves Survival Of Endotoxemic Micementioning

confidence: 99%

A Purified Capsular Polysaccharide Markedly Inhibits Inflammatory Response during Endotoxic Shock

et al. 2013

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“…Lungs were then excised, weighed, and macerated in PBS with a cell strainer for cytokine determination using the DuoSet ELISA development system kit (R&D System). Interleukins 17 and 10 (IL-17 and IL-10) and tumor necrosis factor alpha (TNF-␣) were chosen as the prototypes for cytokine tests based on previous literature on the anticryptococcal immunity (11,32) and chitin-induced cellular responses (15,16). Cytokine contents were normalized to the mass of lungs removed from each animal.…”

Section: Methodsmentioning

confidence: 99%

Chitin-Like Molecules Associate with Cryptococcus neoformans Glucuronoxylomannan To Form a Glycan Complex with Previously Unknown Properties

et al. 2012

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ABSTRACTIn prior studies, we demonstrated that glucuronoxylomannan (GXM), the major capsular polysaccharide of the fungal pathogenCryptococcus neoformans, interacts with chitin oligomers at the cell wall-capsule interface. The structural determinants regulating these carbohydrate-carbohydrate interactions, as well as the functions of these structures, have remained unknown. In this study, we demonstrate that glycan complexes composed of chitooligomers and GXM are formed during fungal growth and macrophage infection byC. neoformans. To investigate the required determinants for the assembly of chitin-GXM complexes, we developed a quantitative scanning electron microscopy-based method using different polysaccharide samples as inhibitors of the interaction of chitin with GXM. This assay revealed that chitin-GXM association involves noncovalent bonds and large GXM fibers and depends on theN-acetyl amino group of chitin. Carboxyl andO-acetyl groups of GXM are not required for polysaccharide-polysaccharide interactions. Glycan complex structures composed of cryptococcal GXM and chitin-derived oligomers were tested for their ability to induce pulmonary cytokines in mice. They were significantly more efficient than either GXM or chitin oligomers alone in inducing the production of lung interleukin 10 (IL-10), IL-17, and tumor necrosis factor alpha (TNF-α). These results indicate that association of chitin-derived structures with GXM through theirN-acetyl amino groups generates glycan complexes with previously unknown properties.

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“…Similar alterations in STAT1 and STAT3 have been observed in rheumatoid arthritis (RA) and have been attributed to activation of TNF-α (22)(23)(24). We therefore assessed the serum levels of TNF-α.…”

mentioning

confidence: 99%

Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

Simonaro¹,

Ge²,

Eliyahu³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

170

175

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Enzyme replacement therapy is currently available for three of the mucopolysaccharidoses (MPSs) but has limited effects on the skeletal lesions. We investigated the involvement of the Toll-like receptor 4 (TLR4) signaling pathway in the pathogenesis of MPS bone and joint disease, and the use of the anti-TNF-α drug, Remicade (Centocor, Inc.), for treatment. TLR4 KO (TLR4 (lps−/−) ) mice were interbred with MPS VII mice to produce double-KO (DKO) animals. The DKO mice had longer and thinner faces and longer femora as revealed by micro-computed tomography analysis compared with MPS VII mice. Histological analyses also revealed more organized and thinner growth plates. The serum levels of TNF-α were normalized in the DKO animals, and the levels of phosphorylated STAT1 and STAT3 in articular chondrocytes were corrected. These findings led us to evaluate the effects of Remicade in MPS VI rats. When initiated at 1 month of age, i.v. treatment prevented the elevation of TNF-α, receptor activator of NF-κB, and other inflammatory molecules not only in the blood but in articular chondrocytes and fibroblast-like synoviocytes (FLSs). Treatment of 6-monthold animals also reduced the levels of these molecules to normal. The number of apoptotic articular chondrocytes in MPS VI rats was similarly reduced, with less infiltration of synovial tissue into the underlying bone. These studies revealed the important role of TLR4 signaling in MPS bone and joint disease and suggest that targeting TNF-α may have positive therapeutic effects.bone and joint disease | inflammation | glycosaminoglycans | growth plate

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

Cited by 39 publications

References 49 publications

A Purified Capsular Polysaccharide Markedly Inhibits Inflammatory Response during Endotoxic Shock

A Purified Capsular Polysaccharide Markedly Inhibits Inflammatory Response during Endotoxic Shock

Chitin-Like Molecules Associate with Cryptococcus neoformans Glucuronoxylomannan To Form a Glycan Complex with Previously Unknown Properties

Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

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