Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1beta production in response to beta-glucans and the fungal pathogen, Candida albicans
Rathinam, Vijay A. K.
Kaiser, William J.
Mocarski, Edward S.
Dillon, Christopher P.
Green, Douglas R.
Mayadas, Tanya N.
Levitz, Stuart M.
Hise, Amy G.
Silverman, Neal S.
Fitzgerald, Katherine A.
UMass Chan AffiliationsDepartment of Medicine, Division of Infectious Diseases and Immunology, Program in Innate Immunity
Immunology and Infectious Disease
Immunology of Infectious Disease
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AbstractInflammasomes 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.
SourceJ Immunol. 2014 Sep 1;193(5):2519-30. doi: 10.4049/jimmunol.1400276. Epub 2014 Jul 25. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/34942
First author Sandhya Ganesan is a doctoral student in the Immunology and Microbiology program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.
Related ResourcesLink to Article in PubMed