Effect of NLRP3 deficiency on cytotoxic and IL-1β-producing activities of synthetic candidalysin peptide.

Candidalysin (CL), a hydrophobic peptide toxin secreted by Candida albicans, is a key virulence factor that contributes to cytolysis, tissue damage, and immune activation. CL is thought to exert some of its biological activities, including IL-1β production, through the activation of the NLRP3-inflammasome pathway. To date, the mechanism by which CL affects human NLRP3 is not fully understood. We investigated specific activities of synthetic CL peptides using human-derived NLRP3-deficient cells. Two distinct synthetic CL peptide solutions were prepared: CLd, with CL completely solubilized as nanoparticles in dimethyl sulfoxide, and CLw, with CL partly solubilized in water, and including insoluble microparticles. THP-1 human monocytic cells and NLRP3-deficient THP-1 cells were differentiated into macrophages and stimulated with these peptide solutions. Cell membrane damage, lactate dehydrogenase release, IL-1β production, and caspase-1 activation in stimulated cells were subsequently evaluated. Both CLd and CLw exhibited cytotoxic activities independent of NLRP3. Importantly, CLd induced IL-1β production and caspase-1 activation in an NLRP3-independent manner, whereas these activities in CLw-stimulated cells were entirely NLRP3-dependent, suggesting that the NLRP3-dependent response might be triggered by insoluble microparticles. Our results demonstrate that inherent CL activities can cause cell damage and IL-1β production in an NLRP3-independent manner. Our research advances the elucidation of the role of NLRP3 in CL biological activity, underscoring the necessity for further exploration of the precise mechanisms underlying the NLRP3-independent effects of CL and providing novel insights into the complexity of host-pathogen interactions.

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