@article{0e9fe02fe2624d669b062b2fb95f005d,
title = "HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages",
abstract = "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.",
keywords = "immunometabolism, inflammation, macrophages, pentose phosphate pathway, uropathogenic Escherichia coli",
author = "Gupta, {Kaustav Das} and Divya Ramnath and {von Pein}, {Jessica B.} and Curson, {James E.B.} and Yizhuo Wang and Rishika Abrol and Asha Kakkanat and Moradi, {Shayli Varasteh} and Gunther, {Kimberley S.} and Murthy, {Ambika M.V.} and Stocks, {Claudia J.} and Ronan Kapetanovic and Reid, {Robert C.} and Abishek Iyer and Ilka, {Zoe C.} and Nauseef, {William M.} and Manuel Plan and Lin Luo and Stow, {Jennifer L.} and Kate Schroder and Denuja Karunakaran and Kirill Alexandrov and Shakespear, {Melanie R.} and Schembri, {Mark A.} and Fairlie, {David P.} and Sweet, {Matthew J.}",
note = "Funding Information: This work was supported by an Australian Research Council (ARC) Discovery Project (DP170102321 to M.J.S.), a National Health and Medical Research Council of Australia (NHMRC) Project Grant (APP1047921 to A.I., D.P.F., and M.J.S.), and an NHMRC Ideas Grant (APP1184885 to D.R. and M.J.S.). M.J.S. is supported by an NHMRC Investigator grant (APP1194406), D.P.F. acknowledges an NHMRC Senior Principal Research Fellowship (APP1117017) as well as an NHMRC Investigator grant (APP2009551), and M.R.S. and A.I. were supported by University of Queensland Postdoctoral Fellowships. L.L. was supported by ARC DECRA Fellowship (DE180100524). J.L.S. and K.S. are supported by NHMRC Investigator Grants APP1176209 and APP2009075, respectively. We acknowledge the Institute for Molecular Bioscience Dynamic Imaging Facility for Cancer Biology at The University of Queensland, established with the support of the Australian Cancer Research Foundation; the IMB Mass Spectrometry Facility; the Transgenic Animal Facility of Queensland (a division of The University of Queensland Biological Resources department); and the ARC Centre of Excellence in Advanced Molecular Imaging (CE140100011). Metabolomics Australia is part of the Bioplatforms Australia network, funded through the Australian Government{\textquoteright}s National Collaborative Research Infrastructure Strategy (NCRIS). We thank Prof. Eric Olson and Prof. Rhonda Bassel-Duby for providing Hdac7fl/flmice (UT Southwestern Medical Centre). Funding Information: ACKNOWLEDGMENTS.This work was supported by an Australian Research Council (ARC) Discovery Project (DP170102321 to M.J.S.), a National Health and Medical Research Council of Australia (NHMRC) Project Grant (APP1047921 to A.I., D.P.F., and M.J.S.),and an NHMRC Ideas Grant (APP1184885 to D.R.and M.J.S.).M.J.S.is supported by an NHMRC Investigator grant (APP1194406),D.P.F.acknowledges an NHMRC Senior Principal Research Fellowship (APP1117017) as well as an NHMRC Investigator grant (APP2009551),and M.R.S.and A.I.were supported by University of Queensland Postdoctoral Fellowships.L.L.was supported by ARC DECRAFellowship (DE180100524). J.L.S. and K.S. are supported by NHMRC Investigator Grants APP1176209 and APP2009075, respectively. We acknowledge the Institute for Molecular Bioscience Dynamic Imaging Facility for Cancer Biology at The University of Queensland, established with the support of the Australian Cancer Research Foundation; the IMB Mass Spectrometry Facility; the Transgenic Animal Facility of Queensland (a division of The University of Queensland Biological Resources department); and the ARC Centre of Excellence in Advanced Molecular Imaging (CE140100011). Metabolomics Australia is part of the Bioplatforms Australia network,funded through the Australian Government{\textquoteright}s National Collaborative Research Infrastructure Strategy (NCRIS). We thank Prof. Eric Olson and Prof. Rhonda Bassel-Duby for providing Hdac7fl/flmice (UT Southwestern Medical Centre). Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s).",
year = "2023",
month = jan,
day = "24",
doi = "10.1073/pnas.2212813120",
language = "English",
volume = "120",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "4",
}