87 : Caspase-8 regulates β-glucan induced IL-1β production and cell death

Abstract

Inflammasomes play a crucial role in host defense against a variety of microbial infections through regulating the maturation of the IL-1 family of cytokines as well as pyroptotic cell death. We have previously identified an essential role for the NLRP3-ASC-Caspase-1 inflammasome in IL-1 β production triggered by the fungal pathogen, C. albicans and the importance of this pathway in the clearance of C. albicans in an in vivo mouse model of Oropharyngeal Candidiasis (OPC). Here, we uncovered an important role for the pro-apoptotic caspase, Caspase-8 in IL-1 β production induced by β -glucan, a potent immunostimulatory component of fungal cell walls. We found that β -glucan induced IL-1 β production requires Caspase-8, in addition to the NLRP3-ASC-Caspase-1 inflammasome. We treated bone marrow derived macrophages and dendritic cells from RIP3 −/− Caspase-8 −/− mice with various β -glucan related molecules, such as curdlan, fungal whole glucan particles or heat killed C. albicans, and found that Caspase-8 was required for IL-1 β production with these stimuli but not with canonical inflammasome activators such as silica, nigericin or poly (dA:dT). Of note, Caspase-8 deficiency did not affect β -glucan induced synthesis of pro-IL1 β . In addition, RIP3 −/− Caspase-8 −/− cells were protected from β -glucan induced cell death, whereas RIP3 −/− deficiency did not affect β -glucan induced IL-1 β production or cell death. In contrast to these observations, we found that IL-1 β production and cell death in response to live C. albicans infection was not Caspase-8 dependent, raising the possibility that β -glucan may not be exposed by C. albicans to engage this pathway. This study establishes a key link between Caspase-8 and Caspase-1 in coordinating cytokine secretion and cell death in response to fungal pathogenic patterns, and provides evidence for how pathways leading to inflammation and cell death are intertwined for an effective host immune response.