Phagocytosis of cells dying through autophagy induces inflammasome activation and IL-1β release in human macrophages

Goran Petrovski, Gizem Ayna, Gyöngyike Majai, Judit Hodrea, Szilvia Benko, András Mádi, László Fésüs

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Phagocytosis of naturally dying cells usually blocks inflammatory reactions in host cells. We have recently observed that clearance of cells dying through autophagy leads to a pro-inflammatory response in human macrophages. Investigating this response further, we found that during engulfment of MCF-7 or 293T cells undergoing autophagic death, but not apoptotic or anoikic ones, caspase-1 was activated and IL-1β was processed, then secreted in an MyD88-independent manner. Autophagic dying cells were capable of preventing some LPS-induced pro-inflammatory responses, such as TNFα, IL-6 and IL-8 induction, but synergized with LPS for IL-1β production. Caspase-1 inhibition prevented macrophage IL-1β release triggered by the dying cells and also other pro-inflammatory cytokines which were not formed in the presence of IL-1 receptor antagonist anakinra either. IL-1β secretion was also observed using calreticulin knockdown or necrostatin-treated autophagic MCF-7 cells and it required phagocytosis of the dying cells which led to ATP secretion from macrophages. Blocking K+ efflux during phagocytosis, the presence of apyrase, adding an antagonist of the P2X7 receptor or silencing the nod-like receptor protein NALP3 inhibited IL-1β secretion. These data suggest that during phagocytosis of autophagic dying cells ATP, acting through its receptor, initiates K+ efflux, inflammasome activation and secretion of IL-1β, which initiates further pro-inflammatory events. Thus, autophagic death of malignant cells and their clearance may lead to immunogenic response.

Original languageEnglish
Pages (from-to)321-330
Number of pages10
JournalAutophagy
Volume7
Issue number3
DOIs
Publication statusPublished - Mar 2011

Keywords

  • ATP
  • Autophagic death
  • IL-1β
  • Inflammasome activation
  • MCF-7
  • Phagocytosis
  • Secretion

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Phagocytosis of cells dying through autophagy induces inflammasome activation and IL-1β release in human macrophages'. Together they form a unique fingerprint.

  • Cite this