Cryptococcal glucuronoxylomannan delays translocation of leukocytes across the blood–brain barrier in an animal model of acute bacterial meningitis

Lipovsky, Myriam M.; Tsenova, Liana; Coenjaerts, Frank E. J.; Kaplan, Gilla; Cherniak, Robert; Hoepelman, Andy I. M.

doi:10.1016/s0165-5728(00)00354-4

Cited by 31 publications

(28 citation statements)

References 22 publications

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“…In addition, a limited cellular influx of inflammatory cells was present in the joints of treated animals, likely due to the decreased production of MIP-1␣ and MIP-2 at the joint level. These data are in agreement with previous studies showing the abilities of GXM to limit chemotaxis (19,20) and to suppress the expression of a chemotactic receptor such as C5aR on inflammatory cells (22). The facts that no effect was observed with 50 g of GXM and that similar therapeutic effects were observed with 100 and 200 g of GXM are consistent with the results of earlier in vitro studies (23) and suggest a sharp dose-response curve.…”

Section: Discussionsupporting

confidence: 92%

“…In particular, a secretion of interleukin-10 (IL-10) (41) and an inhibition of the production of proinflammatory cytokines, such as IL-1␤ and tumor necrosis factor alpha (TNF-␣) (42), are observed after in vitro treatment of monocytes/macrophages with GXM. In addition, GXM inhibits the migration of neutrophils in response to IL-8 (19) and delays the translocation of leukocytes across the blood-brain barrier in an animal model of acute bacterial meningitis (20).…”

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confidence: 99%

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Glucuronoxylomannan, the Major Capsular Polysaccharide of Cryptococcus neoformans , Inhibits the Progression of Group B Streptococcal Arthritis

et al. 2004

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Glucuronoxylomannan (GXM), the principal constituent of the Cryptococcus neoformans capsule, modulates the inflammatory response of human monocytes in vitro. Here we examine the efficacy of GXM as a novel anti-inflammatory compound for use against experimental septic arthritis. Arthritis was induced in mice by the intravenous injection of 8 ؋ 10 6 CFU of type IV group B streptococcus (GBS). GXM was administered intravenously in different doses (50, 100, or 200 g/mouse) 1 day before and 1 day after bacterial inoculation. GXM treatment markedly decreased the incidence and severity of articular lesions. Histological findings showed limited periarticular inflammation in the joints of GXM-treated mice, confirming the clinical observations. The amelioration of arthritis was associated with a significant reduction in the local production of interleukin-6 (IL-6), IL-1␤, macrophage inflammatory protein 1␣ (MIP-1␣), and MIP-2 and an increase in systemic IL-10 levels. Moreover, peritoneal macrophages derived from GXM-treated mice and stimulated in vitro with heat-inactivated GBS showed a similar pattern of cytokine production. The present study provides evidence for the modulation of the inflammatory response by GXM in vivo and suggests a potential therapeutic use for this compound in pathologies involving inflammatory processes.

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

Glucuronoxylomannan, the Major Capsular Polysaccharide of Cryptococcus neoformans , Inhibits the Progression of Group B Streptococcal Arthritis

et al. 2004

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“…Since GXM and mannoprotein 4 have intrinsic chemoattracting properties (10, 15, 16) and high titers of both are found in the bloodstream during infections (10, 13, 25), it has been hypothesized that these compounds, by cross-desensitization, prevent leukocytes from properly responding to chemoattractants, thereby contributing to the scant infiltrate often reported in cryptococcal infections. This has already been demonstrated for GXM in humans as well as in experimental infections in animal models (17,48,49,50). Another mechanism for the diminished leukocyte transendothelial migration, one not yet analyzed in detail in the literature, could be the interference with leukocyte adhesion to the endothelium at the site of infection.…”

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confidence: 80%

Cryptococcal Glucuronoxylomannan Inhibits Adhesion of Neutrophils to Stimulated Endothelium In Vitro by Affecting Both Neutrophils and Endothelial Cells

et al. 2002

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Cryptococcal infections are often characterized by a paucity of leukocytes in the infected tissues. Previous research has shown that the capsular polysaccharide glucuronoxylomannan (GXM) inhibits leukocyte migration. In this study we investigated whether the capsular polysaccharide GXM affects the migration of neutrophils (polymorphonuclear leukocytes [PMN]) through the endothelium by interfering with adhesion in a static adhesion model. Pretreatment of PMN with GXM inhibited PMN adhesion to tumor necrosis factor alpha (TNF-␣)-stimulated endothelium up to 44%. Treatment of TNF-␣-stimulated endothelium with GXM led to a 27% decrease in PMN adhesion. GXM treatment of both PMN and endothelium did not have an additive inhibitory effect. We demonstrated that GXM-induced L-selectin shedding does not play an important role in the detected inhibition of adhesion. L-selectin was still present on PMN in sufficient amounts after GXM treatment, since it could be further inhibited by blocking antibodies. Furthermore, blocking of GXM-related L-selectin shedding did not abolish the GXM-related inhibition of adhesion. GXM most likely exerts its effect on PMN by interfering with E-selectin-mediated binding. The use of blocking monoclonal antibodies against E-selectin, which was shown to decrease adhesion in the absence of GXM, did not cause additive inhibition of PMN adhesion after GXM pretreatment. The use of blocking antibodies also demonstrated that the inhibiting effect found after GXM treatment of endothelium probably involves interference with both intercellular adhesion molecule-1 and E-selectin binding.Cryptococcus neoformans is an encapsulated yeast that can cause life-threatening meningitis in immunocompromised patients. Compared to bacterial meningitis, cryptococcal meningitis is usually characterized by a relative paucity of leukocytes in the cerobrospinal fluid and infected tissues (4, 6), despite adequate stimulation of cytokine production (6,7,12,46,60,65,67). Previous research has shown that the immunomodulatory effects of cryptococcal capsular polysaccharides contribute to the scant leukocyte infiltrates often observed. Cryptococcal culture filtrate, the isolated capsular polysaccharide glucuronoxylomannan (GXM), and mannoprotein 4 (10) all inhibit the influx of leukocytes into inflammation sites (10, 17, 48). Since GXM and mannoprotein 4 have intrinsic chemoattracting properties (10, 15, 16) and high titers of both are found in the bloodstream during infections (10, 13, 25), it has been hypothesized that these compounds, by cross-desensitization, prevent leukocytes from properly responding to chemoattractants, thereby contributing to the scant infiltrate often reported in cryptococcal infections. This has already been demonstrated for GXM in humans as well as in experimental infections in animal models (17,48,49,50). Another mechanism for the diminished leukocyte transendothelial migration, one not yet analyzed in detail in the literature, could be the interference with leukocyte adhesion to the endothelium at ...

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“…These agents include heparin (171), the polysaccharide fucoidin (3,42), and the polysaccharide glucuronoxylomannan from the capsule of the yeast Cryptococcus neoformans. Glucuronoxylomannan decreased TNF-␣ levels in the CSF, an effect not studied for the other polysaccharide agents (80). Though rolling is the initial phase of leukocyte transmigration, inhibition of rolling by fucoidin at the time of antibiotic treatment still affected CSF neutrophil numbers, suggesting that treatment with fucoidin may be relevant in the late phase of the disease, which is the important phase clinically (41).…”

Section: Protect Against Injurymentioning

confidence: 99%

Reprogramming the Host Response in Bacterial Meningitis: How Best To Improve Outcome?

et al. 2003

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Despite effective antibiotic therapy, bacterial meningitis is still associated with high morbidity and mortality in both children and adults. Animal studies have shown that the host inflammatory response induced by bacterial products in the subarachnoid space is associated with central nervous system injury. Thus, attenuation of inflammation early in the disease process might improve the outcome. The feasibility of such an approach is demonstrated by the reduction in neurologic sequelae achieved with adjuvant dexamethasone therapy. Increased understanding of the pathways of inflammation and neuronal damage has suggested rational new targets to modulate the host response in bacterial meningitis, but prediction of which agents would be optimal has been difficult. This review compares the future promise of benefit from the use of diverse adjuvant agents. It appears unlikely that inhibition of a single proinflammatory mediator will prove useful in clinical practice, but several avenues to reprogram a wider array of mediators simultaneously are encouraging. Particularly promising are efforts to adjust combinations of cytokines, to inhibit neuronal apoptosis and to enhance brain repair

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Cryptococcal glucuronoxylomannan delays translocation of leukocytes across the blood–brain barrier in an animal model of acute bacterial meningitis

Cited by 31 publications

References 22 publications

Glucuronoxylomannan, the Major Capsular Polysaccharide of Cryptococcus neoformans , Inhibits the Progression of Group B Streptococcal Arthritis

Glucuronoxylomannan, the Major Capsular Polysaccharide of Cryptococcus neoformans , Inhibits the Progression of Group B Streptococcal Arthritis

Cryptococcal Glucuronoxylomannan Inhibits Adhesion of Neutrophils to Stimulated Endothelium In Vitro by Affecting Both Neutrophils and Endothelial Cells

Reprogramming the Host Response in Bacterial Meningitis: How Best To Improve Outcome?

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