Inflammasome Components Coordinate Autophagy and Pyroptosis as Macrophage Responses to Infection

ABSTRACT When microbes contaminate the macrophage cytoplasm, leukocytes undergo a proinflammatory death that is initiated by nucleotide-binding-domain-, leucine-rich-repeat-containing proteins (NLR proteins) that bind and activate caspase-1. We report that these inflammasome components also regulate...

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Autores principales:	Brenda G. Byrne, Jean-Francois Dubuisson, Amrita D. Joshi, Jenny J. Persson, Michele S. Swanson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/404522b7c4ea440996363903bb320f02
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spelling	oai:doaj.org-article:404522b7c4ea440996363903bb320f022021-11-15T15:40:22ZInflammasome Components Coordinate Autophagy and Pyroptosis as Macrophage Responses to Infection10.1128/mBio.00620-122150-7511https://doaj.org/article/404522b7c4ea440996363903bb320f022013-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00620-12https://doaj.org/toc/2150-7511ABSTRACT When microbes contaminate the macrophage cytoplasm, leukocytes undergo a proinflammatory death that is initiated by nucleotide-binding-domain-, leucine-rich-repeat-containing proteins (NLR proteins) that bind and activate caspase-1. We report that these inflammasome components also regulate autophagy, a vesicular pathway to eliminate cytosolic debris. In response to infection with flagellate Legionella pneumophila, C57BL/6J mouse macrophages equipped with caspase-1 and the NLR proteins NAIP5 and NLRC4 stimulated autophagosome turnover. A second trigger of inflammasome assembly, K+ efflux, also rapidly activated autophagy in macrophages that produced caspase-1. Autophagy protects infected macrophages from pyroptosis, since caspase-1-dependent cell death occurred more frequently when autophagy was dampened pharmacologically by either 3-methyladenine or an inhibitor of the Atg4 protease. Accordingly, in addition to coordinating pyroptosis, both (pro-) caspase-1 protein and NLR components of inflammasomes equip macrophages to recruit autophagy, a disposal pathway that raises the threshold of contaminants necessary to trigger proinflammatory leukocyte death. IMPORTANCE An exciting development in the innate-immunity field is the recognition that macrophages enlist autophagy to protect their cytoplasm from infection. Nutrient deprivation has long been known to induce autophagy; how infection triggers this disposal pathway is an active area of research. Autophagy is encountered by many of the intracellular pathogens that are known to trigger pyroptosis, an inflammatory cell death initiated when nucleotide-binding-domain-, leucine-rich-repeat-containing proteins (NLR proteins) activate caspase-1 within inflammasome complexes. Therefore, we tested the hypothesis that NLR proteins and caspase-1 also coordinate autophagy as a barrier to cytosolic infection. By exploiting classical bacterial and mouse genetics and kinetic assays of autophagy, we demonstrate for the first time that, when confronted with cytosolic contamination, primary mouse macrophages rely not only on the NLR proteins NAIP5 and NLRC4 but also on (pro-)caspase-1 protein to mount a rapid autophagic response that wards off proinflammatory cell death.Brenda G. ByrneJean-Francois DubuissonAmrita D. JoshiJenny J. PerssonMichele S. SwansonAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 1 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Brenda G. Byrne Jean-Francois Dubuisson Amrita D. Joshi Jenny J. Persson Michele S. Swanson Inflammasome Components Coordinate Autophagy and Pyroptosis as Macrophage Responses to Infection
description	ABSTRACT When microbes contaminate the macrophage cytoplasm, leukocytes undergo a proinflammatory death that is initiated by nucleotide-binding-domain-, leucine-rich-repeat-containing proteins (NLR proteins) that bind and activate caspase-1. We report that these inflammasome components also regulate autophagy, a vesicular pathway to eliminate cytosolic debris. In response to infection with flagellate Legionella pneumophila, C57BL/6J mouse macrophages equipped with caspase-1 and the NLR proteins NAIP5 and NLRC4 stimulated autophagosome turnover. A second trigger of inflammasome assembly, K+ efflux, also rapidly activated autophagy in macrophages that produced caspase-1. Autophagy protects infected macrophages from pyroptosis, since caspase-1-dependent cell death occurred more frequently when autophagy was dampened pharmacologically by either 3-methyladenine or an inhibitor of the Atg4 protease. Accordingly, in addition to coordinating pyroptosis, both (pro-) caspase-1 protein and NLR components of inflammasomes equip macrophages to recruit autophagy, a disposal pathway that raises the threshold of contaminants necessary to trigger proinflammatory leukocyte death. IMPORTANCE An exciting development in the innate-immunity field is the recognition that macrophages enlist autophagy to protect their cytoplasm from infection. Nutrient deprivation has long been known to induce autophagy; how infection triggers this disposal pathway is an active area of research. Autophagy is encountered by many of the intracellular pathogens that are known to trigger pyroptosis, an inflammatory cell death initiated when nucleotide-binding-domain-, leucine-rich-repeat-containing proteins (NLR proteins) activate caspase-1 within inflammasome complexes. Therefore, we tested the hypothesis that NLR proteins and caspase-1 also coordinate autophagy as a barrier to cytosolic infection. By exploiting classical bacterial and mouse genetics and kinetic assays of autophagy, we demonstrate for the first time that, when confronted with cytosolic contamination, primary mouse macrophages rely not only on the NLR proteins NAIP5 and NLRC4 but also on (pro-)caspase-1 protein to mount a rapid autophagic response that wards off proinflammatory cell death.
format	article
author	Brenda G. Byrne Jean-Francois Dubuisson Amrita D. Joshi Jenny J. Persson Michele S. Swanson
author_facet	Brenda G. Byrne Jean-Francois Dubuisson Amrita D. Joshi Jenny J. Persson Michele S. Swanson
author_sort	Brenda G. Byrne
title	Inflammasome Components Coordinate Autophagy and Pyroptosis as Macrophage Responses to Infection
title_short	Inflammasome Components Coordinate Autophagy and Pyroptosis as Macrophage Responses to Infection
title_full	Inflammasome Components Coordinate Autophagy and Pyroptosis as Macrophage Responses to Infection
title_fullStr	Inflammasome Components Coordinate Autophagy and Pyroptosis as Macrophage Responses to Infection
title_full_unstemmed	Inflammasome Components Coordinate Autophagy and Pyroptosis as Macrophage Responses to Infection
title_sort	inflammasome components coordinate autophagy and pyroptosis as macrophage responses to infection
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/404522b7c4ea440996363903bb320f02
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Inflammasome Components Coordinate Autophagy and Pyroptosis as Macrophage Responses to Infection

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