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

TLDR

Autophagy, a key regulator of cellular homeostasis activated by pathogen-associated molecules, has been shown to influence IL‑1β secretion by macrophages, though the underlying mechanisms remain unclear. The study investigates a novel role for autophagy in controlling IL‑1β production in antigen‑presenting cells. In macrophages stimulated with Toll‑like receptor ligands, pro‑IL‑1β is sequestered into autophagosomes and rapamycin‑induced autophagy promotes its lysosomal degradation, thereby preventing mature cytokine secretion. Inhibition of autophagy enhances NLRP3‑ and TRIF‑dependent IL‑1β processing and secretion, an effect attenuated by reactive oxygen species inhibition but independent of NOX2, and rapamycin treatment in mice lowers LPS‑induced serum IL‑1β, demonstrating that autophagy regulates IL‑1β through pro‑IL‑1β degradation and inflammasome modulation.

Abstract

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