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LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation

The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1β and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable disease states and is considered an attractive therapeutic t...

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Autores principales: Green, Jack P, Swanton, Tessa, Morris, Lucy V, El-Sharkawy, Lina Y, Cook, James, Yu, Shi, Beswick, James, Adamson, Antony D, Humphreys, Neil E, Bryce, Richard, Freeman, Sally, Lawrence, Catherine, Brough, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679132/
https://www.ncbi.nlm.nih.gov/pubmed/33216713
http://dx.doi.org/10.7554/eLife.59704
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author Green, Jack P
Swanton, Tessa
Morris, Lucy V
El-Sharkawy, Lina Y
Cook, James
Yu, Shi
Beswick, James
Adamson, Antony D
Humphreys, Neil E
Bryce, Richard
Freeman, Sally
Lawrence, Catherine
Brough, David
author_facet Green, Jack P
Swanton, Tessa
Morris, Lucy V
El-Sharkawy, Lina Y
Cook, James
Yu, Shi
Beswick, James
Adamson, Antony D
Humphreys, Neil E
Bryce, Richard
Freeman, Sally
Lawrence, Catherine
Brough, David
author_sort Green, Jack P
collection PubMed
description The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1β and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable disease states and is considered an attractive therapeutic target. However, there is much regarding the mechanism of NLRP3 activation that remains unknown. Chloride efflux is suggested as an important step in NLRP3 activation, but which chloride channels are involved is still unknown. We used chemical, biochemical, and genetic approaches to establish the importance of chloride channels in the regulation of NLRP3 in murine macrophages. Specifically, we identify LRRC8A, an essential component of volume-regulated anion channels (VRAC), as a vital regulator of hypotonicity-induced, but not DAMP-induced, NLRP3 inflammasome activation. Although LRRC8A was dispensable for canonical DAMP-dependent NLRP3 activation, this was still sensitive to chloride channel inhibitors, suggesting there are additional and specific chloride sensing and regulating mechanisms controlling NLRP3.
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spelling pubmed-76791322020-11-23 LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation Green, Jack P Swanton, Tessa Morris, Lucy V El-Sharkawy, Lina Y Cook, James Yu, Shi Beswick, James Adamson, Antony D Humphreys, Neil E Bryce, Richard Freeman, Sally Lawrence, Catherine Brough, David eLife Immunology and Inflammation The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1β and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable disease states and is considered an attractive therapeutic target. However, there is much regarding the mechanism of NLRP3 activation that remains unknown. Chloride efflux is suggested as an important step in NLRP3 activation, but which chloride channels are involved is still unknown. We used chemical, biochemical, and genetic approaches to establish the importance of chloride channels in the regulation of NLRP3 in murine macrophages. Specifically, we identify LRRC8A, an essential component of volume-regulated anion channels (VRAC), as a vital regulator of hypotonicity-induced, but not DAMP-induced, NLRP3 inflammasome activation. Although LRRC8A was dispensable for canonical DAMP-dependent NLRP3 activation, this was still sensitive to chloride channel inhibitors, suggesting there are additional and specific chloride sensing and regulating mechanisms controlling NLRP3. eLife Sciences Publications, Ltd 2020-11-20 /pmc/articles/PMC7679132/ /pubmed/33216713 http://dx.doi.org/10.7554/eLife.59704 Text en © 2020, Green et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Green, Jack P
Swanton, Tessa
Morris, Lucy V
El-Sharkawy, Lina Y
Cook, James
Yu, Shi
Beswick, James
Adamson, Antony D
Humphreys, Neil E
Bryce, Richard
Freeman, Sally
Lawrence, Catherine
Brough, David
LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation
title LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation
title_full LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation
title_fullStr LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation
title_full_unstemmed LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation
title_short LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation
title_sort lrrc8a is essential for hypotonicity-, but not for damp-induced nlrp3 inflammasome activation
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679132/
https://www.ncbi.nlm.nih.gov/pubmed/33216713
http://dx.doi.org/10.7554/eLife.59704
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