Dectin-2 as a Primary Receptor for NLRP3-inflammasome Activation in Dendritic Cell Responses to Histoplasma capsulatum

Abstract

Abstract Inflammasome is an intracellular protein complex that serves as cytosolic pattern recognition receptor (PRR) to engage with pathogens and to process cytokines of the interleukin-1 (IL-1) family into bioactive molecules. It has been established that interleukin-1β (IL-1β) is important to host defense against Histoplasma capsulatum infection. However, the detailed mechanism of how H. capsulatum induces inflammasome activation leading to IL-1β production has not been studied. Here, we showed in dendritic cells (DCs) that H. capsulatum triggers caspase-1 activation and IL-1β production through NLRP3 inflammasome. By reciprocal blocking of Dectin-1 or Dectin-2 in receptor-deficient DCs, we discovered that while Dectin-2 operates as a primary receptor, Dectin-1 serves as a secondary one for NLRP3 inflammasome. Both receptors trigger Syk-JNK signal pathway to activate both signal 1 (the transcription of Il1b) and signal 2 (activation of caspase-1). While both K+ efflux and cathepsin B (but not ROS) function as signal 2, viable H. capsulatum triggers profound lysosomal rupture leading to cathepsin B release. Our study demonstrates the role of Dectin-2 and Dectin-1 in host defense against H. capsulatum infection through induction of NLRP3 inflammasome activation and IL-1b production in DCs.