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Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation

Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation
Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation

Obesity increases the risk of developing life-threatening metabolic diseases including cardiovascular disease, fatty liver disease, diabetes, and cancer. Efforts to curb the global obesity epidemic and its impact have proven unsuccessful in part by a limited understanding of these chronic progressive diseases. It is clear that low-grade chronic inflammation, or metaflammation, underlies the pathogenesis of obesity-associated type 2 diabetes and atherosclerosis. However, the mechanisms that maintain chronicity and prevent inflammatory resolution are poorly understood. Here, we show that inhibitor of κB kinase epsilon (IKBKE) is a novel regulator that limits chronic inflammation during metabolic disease and atherosclerosis. The pathogenic relevance of IKBKE was indicated by the colocalization with macrophages in human and murine tissues and in atherosclerotic plaques. Genetic ablation of IKBKE resulted in enhanced and prolonged priming of the NLRP3 inflammasome in cultured macrophages, in hypertrophic adipose tissue, and in livers of hypercholesterolemic mice. This altered profile associated with enhanced acute phase response, deregulated cholesterol metabolism, and steatoheptatitis. Restoring IKBKE only in hematopoietic cells was sufficient to reverse elevated inflammasome priming and these metabolic features. In advanced atherosclerotic plaques, loss of IKBKE and hematopoietic cell restoration altered plaque composition. These studies reveal a new role for hematopoietic IKBKE: To limit inflammasome priming and metaflammation.

IKBKE, Immunometabolism, Inflammasome, Metabolic disease, Metaflammation
0027-8424
506-511
Patel, Meghana N.
440930f7-4d3e-4f3b-8309-90039afe3ddb
Bernard, William G.
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Milev, Nikolay B.
356e8de6-bec4-436d-9ee6-fe543aa8cc93
Cawthorn, William P.
3eadef28-0866-4a73-81e7-f08db6f7d731
Figg, Nichola
88e24f82-2a9c-4a2a-a451-5843aeeccd25
Hart, Dan
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Prieur, Xavier
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Virtue, Sam
5a5860ed-b7a9-4bee-a2cc-50a019b5bc5c
Hegyi, Krisztina
ba174082-24e9-4b49-abec-b35f68269a79
Bonnafous, Stephanie
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Bailly-Maitre, Beatrice
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Chuf, Yajing
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Griffinf, Julian L.
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Mallat, Ziad
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Considineh, Robert V.
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Tranc, Albert
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Gual, Philippe
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Takeuchi, Osamu
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Akira, Shizuo
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Vidal-Pui, Antonio
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Bennett, Martin R.
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Sethi, Jaswinder K.
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Patel, Meghana N.
440930f7-4d3e-4f3b-8309-90039afe3ddb
Bernard, William G.
3b014ac4-5c36-4958-8dca-953fab4d50b4
Milev, Nikolay B.
356e8de6-bec4-436d-9ee6-fe543aa8cc93
Cawthorn, William P.
3eadef28-0866-4a73-81e7-f08db6f7d731
Figg, Nichola
88e24f82-2a9c-4a2a-a451-5843aeeccd25
Hart, Dan
0e2d6ce5-45b2-4737-bfcc-638561abf551
Prieur, Xavier
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Virtue, Sam
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Hegyi, Krisztina
ba174082-24e9-4b49-abec-b35f68269a79
Bonnafous, Stephanie
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Bailly-Maitre, Beatrice
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Chuf, Yajing
4b9ec374-2a20-4de2-a191-3f25161045ba
Griffinf, Julian L.
fe971a64-84ca-4452-a49a-ed143fa811e7
Mallat, Ziad
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Considineh, Robert V.
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Tranc, Albert
9ace5f63-3942-4cd0-b792-a3c2584fc94b
Gual, Philippe
4ccf6467-df71-483a-86c0-6298385534ef
Takeuchi, Osamu
408f5f16-7a55-4a3e-bd8d-b2aee4a8a88e
Akira, Shizuo
107f806c-9b26-4bf6-b026-963721633d68
Vidal-Pui, Antonio
9c9372a5-4390-4848-a377-0ba256056d21
Bennett, Martin R.
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Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85

Patel, Meghana N., Bernard, William G., Milev, Nikolay B., Cawthorn, William P., Figg, Nichola, Hart, Dan, Prieur, Xavier, Virtue, Sam, Hegyi, Krisztina, Bonnafous, Stephanie, Bailly-Maitre, Beatrice, Chuf, Yajing, Griffinf, Julian L., Mallat, Ziad, Considineh, Robert V., Tranc, Albert, Gual, Philippe, Takeuchi, Osamu, Akira, Shizuo, Vidal-Pui, Antonio, Bennett, Martin R. and Sethi, Jaswinder K. (2015) Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation. Proceedings of the National Academy of Sciences, 112 (2), 506-511. (doi:10.1073/pnas.1414536112).

Record type: Article

Abstract

Obesity increases the risk of developing life-threatening metabolic diseases including cardiovascular disease, fatty liver disease, diabetes, and cancer. Efforts to curb the global obesity epidemic and its impact have proven unsuccessful in part by a limited understanding of these chronic progressive diseases. It is clear that low-grade chronic inflammation, or metaflammation, underlies the pathogenesis of obesity-associated type 2 diabetes and atherosclerosis. However, the mechanisms that maintain chronicity and prevent inflammatory resolution are poorly understood. Here, we show that inhibitor of κB kinase epsilon (IKBKE) is a novel regulator that limits chronic inflammation during metabolic disease and atherosclerosis. The pathogenic relevance of IKBKE was indicated by the colocalization with macrophages in human and murine tissues and in atherosclerotic plaques. Genetic ablation of IKBKE resulted in enhanced and prolonged priming of the NLRP3 inflammasome in cultured macrophages, in hypertrophic adipose tissue, and in livers of hypercholesterolemic mice. This altered profile associated with enhanced acute phase response, deregulated cholesterol metabolism, and steatoheptatitis. Restoring IKBKE only in hematopoietic cells was sufficient to reverse elevated inflammasome priming and these metabolic features. In advanced atherosclerotic plaques, loss of IKBKE and hematopoietic cell restoration altered plaque composition. These studies reveal a new role for hematopoietic IKBKE: To limit inflammasome priming and metaflammation.

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More information

Accepted/In Press date: 2 December 2014
e-pub ahead of print date: 13 January 2015
Keywords: IKBKE, Immunometabolism, Inflammasome, Metabolic disease, Metaflammation

Identifiers

Local EPrints ID: 415251
URI: https://eprints.soton.ac.uk/id/eprint/415251
ISSN: 0027-8424
PURE UUID: ad86fc0a-ac2c-48bf-ac2c-ca9f322ebe80
ORCID for Jaswinder K. Sethi: ORCID iD orcid.org/0000-0003-4157-0475

Catalogue record

Date deposited: 06 Nov 2017 17:30
Last modified: 14 Mar 2019 01:25

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Contributors

Author: Meghana N. Patel
Author: William G. Bernard
Author: Nikolay B. Milev
Author: William P. Cawthorn
Author: Nichola Figg
Author: Dan Hart
Author: Xavier Prieur
Author: Sam Virtue
Author: Krisztina Hegyi
Author: Stephanie Bonnafous
Author: Beatrice Bailly-Maitre
Author: Yajing Chuf
Author: Julian L. Griffinf
Author: Ziad Mallat
Author: Robert V. Considineh
Author: Albert Tranc
Author: Philippe Gual
Author: Osamu Takeuchi
Author: Shizuo Akira
Author: Antonio Vidal-Pui
Author: Martin R. Bennett

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