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

Autor:	Das Gupta K; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Ramnath D; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., von Pein JB; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Curson JEB; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Wang Y; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Abrol R; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Kakkanat A; School of Chemistry and Molecular Biosciences, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Moradi SV; The Commonwealth Scientific and Industrial Research Organisation-Queensland University of Technology Synthetic Biology Alliance, Australian Research Council Centre of Excellence in Synthetic Biology, School of Biology and Environmental Science, Queensland University of Technology, Brisbane, QLD 4001, Australia., Gunther KS; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Murthy AMV; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Stocks CJ; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Kapetanovic R; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Reid RC; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Iyer A; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Ilka ZC; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Nauseef WM; Department of Internal Medicine, Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA 52242., Plan M; Metabolomics Australia (Queensland Node), Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia., Luo L; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Stow JL; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Schroder K; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Karunakaran D; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Alexandrov K; The Commonwealth Scientific and Industrial Research Organisation-Queensland University of Technology Synthetic Biology Alliance, Australian Research Council Centre of Excellence in Synthetic Biology, School of Biology and Environmental Science, Queensland University of Technology, Brisbane, QLD 4001, Australia., Shakespear MR; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Schembri MA; School of Chemistry and Molecular Biosciences, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Fairlie DP; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia., Sweet MJ; Institute for Molecular Bioscience, Institute for Molecular Bioscience Centre for Inflammation and Disease Research, and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Jan 24; Vol. 120 (4), pp. e2212813120. Date of Electronic Publication: 2023 Jan 17.
DOI:	10.1073/pnas.2212813120
Abstrakt:	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.
Databáze:	MEDLINE
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