Autophagy Controls IL-1β Secretion by Targeting Pro-IL-1β for Degradation

Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1 beta secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1 beta in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1 beta was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1 beta and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1 beta by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1 beta in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1 beta through at least two separate mechanisms: by targeting pro-IL-1 beta for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.