Polyene Macrolide Antifungal Drugs Trigger Interleukin-1β Secretion by Activating the NLRP3 Inflammasome

The use of antimycotic drugs in fungal infections is based on the concept that they suppress fungal growth by a direct killing effect. However, amphotericin and nystatin have been reported to also trigger interleukin-1 beta (IL-1 beta) secretion in monocytes but the molecular mechanism is unknown. Here we report that only the polyene macrolides amphotericin B, nystatin, and natamycin but none of the tested azole antimycotic drugs induce significant IL-1 beta secretion in-vitro in dendritic cells isolated from C57BL/6 mouse bone marrow. IL-1 beta release depended on Toll-like receptor-mediated induction of pro-IL-1 beta as well as the NLRP3 inflammasome, its adaptor ASC, and caspase-1 for enzymatic cleavage of proIL-1 beta into its mature form. All three drugs induced potassium efflux from the cells as a known mechanism for NLRP3 activation but the P2X7 receptor was not required for this process. Natamycin-induced IL-1 beta secretion also involved phagocytosis, as cathepsin activation as described for crystal-induced IL-1 beta release. Together, the polyene macrolides amphotericin B, nystatin, and natamycin trigger IL-1 beta secretion by causing potassium efflux from which activates the NLRP3-ASC-caspase-1. We conclude that beyond their effects on fungal growth, these antifungal drugs directly activate the host's innate immunity.