Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1beta production in response to beta-glucans and the fungal pathogen, Candida albicans
Department of Medicine, Division of Infectious Diseases and Immunology, Program in Innate Immunity
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-1beta maturation and resistance to fungal dissemination in Candida albicans infection. beta-Glucans are major components of fungal cell walls that trigger IL-1beta secretion in both murine and human immune cells. In this study, we sought to determine the contribution of beta-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-1beta production in response to beta-glucans. Interestingly, we also found that both complement receptor 3 (CR3) and dectin-1 play a crucial role in coordinating beta-glucan-induced IL-1beta 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 beta-glucan-induced cell death and NLRP3 inflammasome-dependent IL-1beta maturation. A strong requirement for CR3 and caspase-8 also was found for NLRP3-dependent IL-1beta 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 beta-glucan- and C. albicans-induced innate responses in dendritic cells. Collectively, these findings establish a novel link between beta-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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Citation: J Immunol. 2014 Sep 1;193(5):2519-30. doi: 10.4049/jimmunol.1400276. Epub 2014 Jul 25. Link to article on publisher's site
Ganesan, Sandhya; Rathinam, Vijay A. K.; Bossaller, Lukas; Army, Kelly; Kaiser, William J.; Mocarski, Edward S.; Dillon, Christopher P.; Green, Douglas R.; Mayadas, Tanya N.; Levitz, Stuart M.; Hise, Amy G.; Silverman, Neal S.; and Fitzgerald, Katherine A., "Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1beta production in response to beta-glucans and the fungal pathogen, Candida albicans" (2014). Infectious Diseases and Immunology Publications and Presentations. 165.