Glucuronoxylomannan, the major capsular polysaccharide of Cryptococcus neoformans, inhibits the progression of group B streptococcal arthritis

Abstract

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 x 10(6) CFU of type IV group B streptococcus (GBS). GXM was administered intravenously in different doses (50, 100, or 200 microg/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-1beta, macrophage inflammatory protein 1alpha (MIP-1alpha), 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.

FIG. 1.

Effect of GXM treatment on incidence and severity of arthritis in mice infected with GBS. GXM (100 or 200 μg/mouse) was administered 1 day before and 1 day after infection with 8 × 10⁶ CFU of GBS/mouse. Ten mice were used for each experimental group. (A) Incidence of arthritis. Values represent the means ± SD of three separate experiments, each consisting of 10 animals per experimental group. •, P < 0.05; ‡, P < 0.01 (for GXM-treated versus control mice, according to Fisher's exact test). (B) Arthritis index. Values represent the means ± SD of three separate experiments, each consisting of 10 animals per experimental group. *, P < 0.01 (for GXM-treated versus control mice, according to unpaired Student's t test).

FIG. 2.

Histopathological evaluation of GBS-induced arthritis after systemic administration of GXM. (A) Histopathological severity of arthritis (for 100 μg of GXM, 10 paws and 24 joints were assessed; for 200 μg of GXM, 10 paws and 22 joints were assessed; for saline treatment, 10 paws and 28 joints were assessed). •, P < 0.05 (for GXM-treated versus control mice, according to χ² test). (B) Severe arthritis in a control mouse, with presence of massive infiltrate and evidence of cartilage degradation. (C) Upon GXM treatment, the presence of infiltrate was limited to subcutaneous and muscular tissues, with a maintenance of cartilage integrity (original magnification, ×10).

FIG. 3.

Effect of GXM treatment on cytokine and chemokine production in joints of GBS-infected mice. Mice were treated with GXM (100 μg/mouse) 1 day before and 1 day after infection with 8 × 10⁶ CFU of GBS/mouse. Day 0 represents uninfected mice. Data represent the means ± SD of three separate experiments. Three mice per group were sacrificed at each indicated time point. *, P < 0.01 (for GXM-treated versus control mice, according to unpaired Student's t test).

FIG. 4.

Cytokine and chemokine production from peritoneal macrophages derived from GXM-treated mice and stimulated in vitro with GBS. Mice were injected intraperitoneally with 1 ml of 10% thioglycolate and then treated with GXM (100 μg/mouse) or saline the same day and 2 days after thioglycolate injection. Peritoneal macrophages were then recovered and stimulated as described in Materials and Methods. Data represent the means ± SD of three separate experiments. •, P < 0.05; *, P < 0.01 (for GXM-treated versus control mice, according to unpaired Student's t test).