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

Adjuvant Research Group, School of Biochemistry and Immunology, Trinity College Dublin, College Green, Dublin 2, Ireland.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2011; 286(11):9587-97. DOI: 10.1074/jbc.M110.202911
Source: PubMed

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.

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Available from: James Harris, Sep 01, 2015
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    • "Further studies focused on how autophagy regulated IL-1β secretion. Harris et al. found that pro-IL-1β is targeted by autophagosomes and degraded following exposure of macrophages to various TLR agonists [57]. Another study investigated inflammasome activity in macrophages from mice deficient in other autophagy-related proteins. "
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    • "While basal autophagy prevents inflammation, e.g., by limiting mitochondrial generation of reactive oxygen species and the resulting inflammasome activation (48, 49), induction of autophagy can promote inflammation, mediating the inflammasome-dependent unconventional release of the endogenous pyrogen, IL-1β, which in turn can intensify autophagy (50). Autophagy may also yield negative feedback loops to prevent destructive inflammation, e.g., moderating IL-1β release by targeting inflammasomes and pro-IL-1β for degradation (51, 52). "
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