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HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages

The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response....

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Autores principales: Das Gupta, Kaustav, Ramnath, Divya, von Pein, Jessica B., Curson, James E. B., Wang, Yizhuo, Abrol, Rishika, Kakkanat, Asha, Moradi, Shayli Varasteh, Gunther, Kimberley S., Murthy, Ambika M. V., Stocks, Claudia J., Kapetanovic, Ronan, Reid, Robert C., Iyer, Abishek, Ilka, Zoe C., Nauseef, William M., Plan, Manuel, Luo, Lin, Stow, Jennifer L., Schroder, Kate, Karunakaran, Denuja, Alexandrov, Kirill, Shakespear, Melanie R., Schembri, Mark A., Fairlie, David P., Sweet, Matthew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942870/
https://www.ncbi.nlm.nih.gov/pubmed/36649417
http://dx.doi.org/10.1073/pnas.2212813120
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author Das Gupta, Kaustav
Ramnath, Divya
von Pein, Jessica B.
Curson, James E. B.
Wang, Yizhuo
Abrol, Rishika
Kakkanat, Asha
Moradi, Shayli Varasteh
Gunther, Kimberley S.
Murthy, Ambika M. V.
Stocks, Claudia J.
Kapetanovic, Ronan
Reid, Robert C.
Iyer, Abishek
Ilka, Zoe C.
Nauseef, William M.
Plan, Manuel
Luo, Lin
Stow, Jennifer L.
Schroder, Kate
Karunakaran, Denuja
Alexandrov, Kirill
Shakespear, Melanie R.
Schembri, Mark A.
Fairlie, David P.
Sweet, Matthew J.
author_facet Das Gupta, Kaustav
Ramnath, Divya
von Pein, Jessica B.
Curson, James E. B.
Wang, Yizhuo
Abrol, Rishika
Kakkanat, Asha
Moradi, Shayli Varasteh
Gunther, Kimberley S.
Murthy, Ambika M. V.
Stocks, Claudia J.
Kapetanovic, Ronan
Reid, Robert C.
Iyer, Abishek
Ilka, Zoe C.
Nauseef, William M.
Plan, Manuel
Luo, Lin
Stow, Jennifer L.
Schroder, Kate
Karunakaran, Denuja
Alexandrov, Kirill
Shakespear, Melanie R.
Schembri, Mark A.
Fairlie, David P.
Sweet, Matthew J.
author_sort Das Gupta, Kaustav
collection PubMed
description The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response. Lipopolysaccharide (LPS) and soluble signals indicating distal or far-away danger trigger HDAC7-dependent glycolysis and proinflammatory IL-1β production. In contrast, HDAC7 initiates the pentose phosphate pathway (PPP) for NADPH and reactive oxygen species (ROS) production in response to the more proximal threat of nearby bacteria, as exemplified by studies on uropathogenic Escherichia coli (UPEC). HDAC7-mediated PPP engagement via 6-phosphogluconate dehydrogenase (6PGD) generates NADPH for antimicrobial ROS production, as well as D-ribulose-5-phosphate (RL5P) that both synergizes with ROS for UPEC killing and suppresses selective inflammatory responses. This dual functionality of the HDAC7-6PGD-RL5P axis prioritizes responses to proximal threats. Our findings thus reveal that the PPP metabolite RL5P has both antimicrobial and immunomodulatory activities and that engagement of enzymes in catabolic versus anabolic metabolic pathways triages responses to different types of danger for generation of inflammatory versus antimicrobial responses, respectively.
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spelling pubmed-99428702023-07-17 HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages Das Gupta, Kaustav Ramnath, Divya von Pein, Jessica B. Curson, James E. B. Wang, Yizhuo Abrol, Rishika Kakkanat, Asha Moradi, Shayli Varasteh Gunther, Kimberley S. Murthy, Ambika M. V. Stocks, Claudia J. Kapetanovic, Ronan Reid, Robert C. Iyer, Abishek Ilka, Zoe C. Nauseef, William M. Plan, Manuel Luo, Lin Stow, Jennifer L. Schroder, Kate Karunakaran, Denuja Alexandrov, Kirill Shakespear, Melanie R. Schembri, Mark A. Fairlie, David P. Sweet, Matthew J. Proc Natl Acad Sci U S A Biological Sciences The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response. Lipopolysaccharide (LPS) and soluble signals indicating distal or far-away danger trigger HDAC7-dependent glycolysis and proinflammatory IL-1β production. In contrast, HDAC7 initiates the pentose phosphate pathway (PPP) for NADPH and reactive oxygen species (ROS) production in response to the more proximal threat of nearby bacteria, as exemplified by studies on uropathogenic Escherichia coli (UPEC). HDAC7-mediated PPP engagement via 6-phosphogluconate dehydrogenase (6PGD) generates NADPH for antimicrobial ROS production, as well as D-ribulose-5-phosphate (RL5P) that both synergizes with ROS for UPEC killing and suppresses selective inflammatory responses. This dual functionality of the HDAC7-6PGD-RL5P axis prioritizes responses to proximal threats. Our findings thus reveal that the PPP metabolite RL5P has both antimicrobial and immunomodulatory activities and that engagement of enzymes in catabolic versus anabolic metabolic pathways triages responses to different types of danger for generation of inflammatory versus antimicrobial responses, respectively. National Academy of Sciences 2023-01-17 2023-01-24 /pmc/articles/PMC9942870/ /pubmed/36649417 http://dx.doi.org/10.1073/pnas.2212813120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Das Gupta, Kaustav
Ramnath, Divya
von Pein, Jessica B.
Curson, James E. B.
Wang, Yizhuo
Abrol, Rishika
Kakkanat, Asha
Moradi, Shayli Varasteh
Gunther, Kimberley S.
Murthy, Ambika M. V.
Stocks, Claudia J.
Kapetanovic, Ronan
Reid, Robert C.
Iyer, Abishek
Ilka, Zoe C.
Nauseef, William M.
Plan, Manuel
Luo, Lin
Stow, Jennifer L.
Schroder, Kate
Karunakaran, Denuja
Alexandrov, Kirill
Shakespear, Melanie R.
Schembri, Mark A.
Fairlie, David P.
Sweet, Matthew J.
HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages
title HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages
title_full HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages
title_fullStr HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages
title_full_unstemmed HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages
title_short HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages
title_sort hdac7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942870/
https://www.ncbi.nlm.nih.gov/pubmed/36649417
http://dx.doi.org/10.1073/pnas.2212813120
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