Cryptococcus neoformans glucuronoxylomannan induces macrophage apoptosis mediated by nitric oxide in a caspase-independent pathway

CHIAPELLO LS, BARONETTI JL, GARRO AP, SPESSO MF, MASIH DT

INTERNATIONAL IMMUNOLOGY

Oxford Journals

Año: 2008 vol. 20 p. 1527 - 1541

0953-8178

Glucuronoxylomannan (GXM) is the major component of Cryptococcus capsular polysaccharide, which represents an essential virulence factor for this yeast. Cryptococcus neoformans infections in immunocompetent rats are associated with inducible NO synthase (iNOS) expression and nitric oxide (NO) production by macrophages. This study demonstrates in vitro and in vivo that GXM promotes iNOS expression with NO production in rat macrophages. GXM also induced macrophage apoptosis after 48 h of culture, with this phenomenon being prevented by the iNOS inhibitor, aminoguanidine. The NO-induced macrophage apoptosis triggered by GXM was dependent on interactions with CD18, FcgRII receptors and protein kinase C activation, without participation of tyrosine kinases or mitogen-activated protein kinases (MAPK). Furthermore, this study reveals that GXM downregulates the macrophage caspase-3 activity, induces a caspase-independent cell death, and promotes depolarization of mitochondria membrane potential with increased cytosolic expression of the apoptosis-inducing factor (AIF). Taken together, this study describes the pathways and mechanisms involved in the macrophage apoptosis promoted by GXM through NO generation. These findings indicate new mechanisms of immunomodulation for the main capsular polysaccharide of C. neoformans.