Capsular polysaccharide induction of apoptosis by intrinsic and extrinsic mechanisms
Claudia Monari1, Francesca Paganelli, Francesco Bistoni
1Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Abstract:
A purified microbial capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan (GXM), induces Fas ligand (FasL) upregulation on macrophages and, as a consequence, apoptosis of lymphocytes. The mechanisms that lead to lymphocyte apoptosis in both in vitro and in vivo systems were investigated by cytofluorimetric analysis and Western blotting experiments. Caspase 8 cleaves caspase 3 in two different pathways: directly as well as indirectly by activation of Bcl-2 interacting domain, which initiates caspase 9 cleavage. Therefore, the caspase 8 and caspase 9 pathways cooperate in an amplification loop for efficient cell death, and noteworthily we provide evidence that they are both activated in one single cell. Furthermore, both activation of GXM-mediated caspase 8 and apoptosis were also found in in vivo systems in an experimental model of murine candidiasis. Collectively, our data show that GXM-induced apoptosis involves, in a single cell, a cross-talk between extrinsic and intrinsic pathways. Such a finding offers opportunities for the therapeutic usage of this polysaccharide in appropriate clinical settings for taming T-cell responses.
Insights
Glucuronoxylomannan (GXM) from Cryptococcus neoformans triggers lymphocyte apoptosis by activating both extrinsic and intrinsic cell death pathways within a single cell. This mechanism offers potential for therapeutic applications in modulating T-cell responses.
Area of Science:
- Immunology
- Cell Biology
- Microbial Pathogenesis
Background:
- Cryptococcus neoformans glucuronoxylomannan (GXM) induces lymphocyte apoptosis via Fas ligand (FasL) on macrophages.
- Understanding the precise molecular mechanisms of GXM-induced apoptosis is crucial for exploring therapeutic interventions.
Purpose of the Study:
- To elucidate the molecular pathways mediating GXM-induced lymphocyte apoptosis in vitro and in vivo.
- To investigate the interplay between extrinsic and intrinsic apoptotic pathways in GXM-treated cells.
Main Methods:
- Cytofluorimetric analysis to assess cellular events.
- Western blotting to detect protein cleavage and activation.
- Experimental model of murine candidiasis for in vivo validation.
Main Results:
- GXM upregulates FasL on macrophages, leading to lymphocyte apoptosis.
- Both caspase 8 (extrinsic) and caspase 9 (intrinsic) pathways are activated within the same cell, forming an amplification loop.
- GXM-mediated caspase 8 activation and apoptosis were confirmed in a murine candidiasis model.
Conclusions:
- GXM-induced apoptosis involves a coordinated cross-talk between extrinsic and intrinsic apoptotic pathways within a single cell.
- This intricate apoptotic mechanism highlights GXM's potential for therapeutic use in controlling T-cell-mediated immune responses.
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