Vue d'ensemble de la session
Tuesday, July 23

Chairs: Pr. Matt Sweet, Institute for Molecular Bioscience, Australia, Pr. Phil Hansbro, Centenary Institute and University of Technology Sydney, Australia

Summary TBA

Metabolic features of mucosal tissues shaping inflammatory disease
Dr. Gabrielle Belz, Frazer Institute and The University of Queensland, Australia

Clonal haematopoiesis is influenced by metabolic disorders
Dr. Andrew Murphy, Baker Heart and Diabetes Institute, Australia

An innate immune signalling axis that controls inflammatory cytokine production via regulated immunometabolism
Pr. Matt Sweet, Institute for Molecular Bioscience, Australia

Oxidized Cholesterols Drive Macrophage Recruitment and Inflammation in the Lung
Dr. Katharina Ronacher, Mater Research-UQ, Australia

Matthew Sweet, IMB, The University of Queensland, Australia
Phil Hansbro,

Room: 301B





* Matthew Sweet, IMB, The University of Queensland, Australia
Kaustav Das Gupta, IMB, The University of Queensland, Australia
Divya Ramnath, IMB, The University of Queensland, Australia
Jessica von Pein, IMB, The University of Queensland, Australia
James Curson, IMB, The University of Queensland, Australia
Yizhuo Wang, IMB, The University of Queensland, Australia
Rishika Abrol, IMB, The University of Queensland, Australia
Kimberley Gunther, IMB, The University of Queensland, Australia

Innate immune cells sense danger in different contexts, allowing inflammatory responses to be tailored to the level of threat encountered. Here we describe a metabolic switch that triages threats, either switching on or dampening macrophage inflammatory responses, depending on the type of danger detected. We also reveal novel immunoregulatory properties of the macrophage metabolite ribulose-5-phosphate (RL5P). We show that histone deacetylase 7 (HDAC7) is a cytoplasmic lysine deacetylase in macrophages. When danger signals such as soluble lipopolysaccharide (LPS) indicating far-away or distal danger are detected by macrophages, HDAC7 deacetylates the glycolytic enzyme PKM2 for HIF-1alpha activation and proinflammatory IL-1beta production. In contrast, HDAC7 triggers the pentose phosphate pathway (PPP), NADPH production, and phagocyte oxidase-mediated reactive oxygen species generation for bacterial killing when nearby threats, such as bacteria, are encountered. PPP activation by HDAC7 also suppresses IL-1beta and other inflammatory cytokines, allowing cells to focus resources on bacterial killing. In vivo targeting of HDAC7 compromises antibacterial defense and exacerbates inflammation, highlighting the pivotal role of this pathway during infection. Mechanistically, HDAC7 activates the PPP enzyme 6-phosphogluconate dehydrogenase (6PGD), with the enzymatic product of 6PGD, RL5P, suppressing inflammatory responses in human and mouse macrophages. RL5P also exerts direct antibacterial effects on E. coli exposed to oxidative stress, suggesting this metabolite may also contribute to bacterial killing in the macrophage phagosome. In summary, HDAC7 engages the glycolysis-PKM2-HIF-1alpha axis to drive inflammation when signs of far-away danger are detected, but triggers the PPP-6PGD-RL5P pathway for direct antibacterial defense over proinflammatory cytokine production when nearby danger is encountered. Thus, the HDAC7 immunometabolic switch selects for inflammatory versus antimicrobial responses in macrophages and the HDAC7-6PGD-RL5P axis may be amenable for targeting in inflammation and/or infection.