Caspase-8 modulates dectin-1 and complement receptor 3–driven IL-1β production in response to β-glucans and the fungal pathogen, Candida albicans

S Ganesan, VAK Rathinam, L Bossaller… - The Journal of …, 2014 - journals.aai.org
S Ganesan, VAK Rathinam, L Bossaller, K Army, WJ Kaiser, ES Mocarski, CP Dillon…
The Journal of Immunology, 2014journals.aai.org
Inflammasomes are central mediators of host defense to a wide range of microbial
pathogens. The nucleotide-binding domain and leucine-rich repeat containing family (NLR),
pyrin domain–containing 3 (NLRP3) inflammasome plays a key role in triggering caspase-1–
dependent IL-1β maturation and resistance to fungal dissemination in Candida albicans
infection. β-Glucans are major components of fungal cell walls that trigger IL-1β secretion in
both murine and human immune cells. In this study, we sought to determine the contribution …
Abstract
Inflammasomes are central mediators of host defense to a wide range of microbial pathogens. The nucleotide-binding domain and leucine-rich repeat containing family (NLR), pyrin domain–containing 3 (NLRP3) inflammasome plays a key role in triggering caspase-1–dependent IL-1β maturation and resistance to fungal dissemination in Candida albicans infection. β-Glucans are major components of fungal cell walls that trigger IL-1β secretion in both murine and human immune cells. In this study, we sought to determine the contribution of β-glucans to C. albicans–induced inflammasome responses in mouse dendritic cells. We show that the NLRP3–apoptosis-associated speck-like protein containing caspase recruitment domain protein–caspase-1 inflammasome is absolutely critical for IL-1β production in response to β-glucans. Interestingly, we also found that both complement receptor 3 (CR3) and dectin-1 play a crucial role in coordinating β-glucan–induced IL-1β processing as well as a cell death response. In addition to the essential role of caspase-1, we identify an important role for the proapoptotic protease caspase-8 in promoting β-glucan–induced cell death and NLRP3 inflammasome-dependent IL-1β maturation. A strong requirement for CR3 and caspase-8 also was found for NLRP3-dependent IL-1β production in response to heat-killed C. albicans. Taken together, these results define the importance of dectin-1, CR3, and caspase-8, in addition to the canonical NLRP3 inflammasome, in mediating β-glucan–and C. albicans–induced innate responses in dendritic cells. Collectively, these findings establish a novel link between β-glucan recognition receptors and the inflammatory proteases caspase-8 and caspase-1 in coordinating cytokine secretion and cell death in response to immunostimulatory fungal components.
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