Papillomavirus virus-like particles trigger IL-1beta release through the canonical inflammasome activation signaling pathway (136.33)

Abstract

Abstract Papillomavirus virus-like particles (VLPs), formed by self-assembled caspid L1 protein, are extremely immunogenic. They can be used both as a mucosal delivery vector and an adjuvant for treating human diseases. However, the mechanism(s) by which papillomavirus VLPs function as an adjuvant is still unclear. We hypothesized that papillomavirus VLPs activate inflammasome in antigen-presenting cells to function as an adjuvant. In order to test our hypothesis, we cocultured HPV16, BPV-1 VLPs or a BPV-1 VLP presenting HIV-1 gp41 neutralizing epitope (chimeric HIV-BPV VLPs) respectively with PMA-primed human THP-1 cells and determined IL-1beta release in the presence or absence of inhibitors of the Nlrp3-inflammasome pathway. We found that HPV-16, BPV-1 VLPs and chimeric HIV-BPV VLPs are capable of activating inflammasome in PMA-primed THP-1 cells, which eventually results in the release of IL-1beta. The release of IL-1beta by the VLPs requires the uptake of VLPs by macrophages as inhibition of clathrin-mediated endocytosis blocked IL-1beta release. Furthermore, the inhibition of cathepsin B or caspase-1 abolished IL-1beta release in the presence of the VLPs. Finally, we also found that generation of reactive oxygen species (ROS) is necessary for activating inflammsome since inhibition of ROS production reduced the level of released IL-1beta. Thus, our results demonstrated that papillomavirus VLPs can activate inflammasome through the canonical inflammasome activation pathway.