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

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.

• Authors: Sandhya Ganesan, Vijay A K Rathinam, Lukas Bossaller, Kelly Army, William J Kaiser, Edward S Mocarski, Christopher P Dillon, Douglas R Green, Tanya N Mayadas, Stuart M Levitz, Amy G Hise, Neal Silverman, Katherine A Fitzgerald
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 5 Pg. 2519-2530 (Sep 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 25063877 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carrier Proteins
• Fungal Polysaccharides
• IL1B protein, mouse
• Interleukin-1beta
• Lectins, C-Type
• Macrophage-1 Antigen
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• beta-Glucans
• dectin 1
• Casp8 protein, mouse
• Caspase 8

Topics

• Animals
• Candida albicans (genetics, immunology)
• Candidiasis (genetics, immunology, pathology)
• Carrier Proteins (genetics, immunology)
• Caspase 8 (genetics, immunology)
• Cell Death (genetics, immunology)
• Dendritic Cells (immunology, pathology)
• Fungal Polysaccharides (genetics, immunology)
• Humans
• Interleukin-1beta (genetics, immunology)
• Lectins, C-Type (genetics, immunology)
• Macrophage-1 Antigen (genetics, immunology)
• Mice
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• beta-Glucans (immunology)