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-1β (IL-1β) 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-1β
secretion in-vitro in dendritic cells isolated from C57BL/6 mouse
bone marrow. IL-1β release depended on Toll-like receptor-mediated
induction of pro-IL-1β as well as the NLRP3 inflammasome, its
adaptor ASC, and caspase-1 for enzymatic cleavage of pro-IL-1β 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-1β
secretion also involved phagocytosis, as cathepsin activation as
described for crystal-induced IL-1β release. Together, the polyene
macrolides amphotericin B, nystatin, and natamycin trigger IL-1β
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.