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

G. Petrovski, Gizem Ayna, Gyöngyike Majai, Judit Hodrea, Sz. Benkő, A. Mádi, L. Fésüs

Research output: Article

44 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 P2X 7 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 - márc. 2011

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Inflammasomes
Cytophagocytosis
Autophagy
Interleukin-1
Macrophages
Phagocytosis
Caspase 1
MCF-7 Cells
Adenosine Triphosphate
Apyrase
Calreticulin
Interleukin 1 Receptor Antagonist Protein
Interleukin-1 Receptors
HEK293 Cells
Interleukin-8
Interleukin-6
Cytokines

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

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title = "Phagocytosis of cells dying through autophagy induces inflammasome activation and IL-1β release in human macrophages",
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 P2X 7 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.",
keywords = "ATP, Autophagic death, IL-1β, Inflammasome activation, MCF-7, P2x, Phagocytosis, Secretion",
author = "G. Petrovski and Gizem Ayna and Gy{\"o}ngyike Majai and Judit Hodrea and Sz. Benkő and A. M{\'a}di and L. F{\'e}s{\"u}s",
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T1 - Phagocytosis of cells dying through autophagy induces inflammasome activation and IL-1β release in human macrophages

AU - Petrovski, G.

AU - Ayna, Gizem

AU - Majai, Gyöngyike

AU - Hodrea, Judit

AU - Benkő, Sz.

AU - Mádi, A.

AU - Fésüs, L.

PY - 2011/3

Y1 - 2011/3

N2 - 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 P2X 7 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.

AB - 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 P2X 7 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.

KW - ATP

KW - Autophagic death

KW - IL-1β

KW - Inflammasome activation

KW - MCF-7

KW - P2x

KW - Phagocytosis

KW - Secretion

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