Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection

Mack B. Reynolds; Benjamin Klein; Michael J. McFadden; Norah K. Judge; Hannah E. Navarrete; Britton C Michmerhuizen; Dominik Awad; Tracey L. Schultz; Paul W. Harms; Li Zhang; Teresa R. O’Meara; Jonathan Z. Sexton; Costas A. Lyssiotis; J. Michelle Kahlenberg; Mary X. O’Riordan

Cell Reports (Aug 2024)

Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection

Mack B. Reynolds,
Benjamin Klein,
Michael J. McFadden,
Norah K. Judge,
Hannah E. Navarrete,
Britton C Michmerhuizen,
Dominik Awad,
Tracey L. Schultz,
Paul W. Harms,
Li Zhang,
Teresa R. O’Meara,
Jonathan Z. Sexton,
Costas A. Lyssiotis,
J. Michelle Kahlenberg,
Mary X. O’Riordan

Affiliations

Mack B. Reynolds: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Benjamin Klein: Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Michael J. McFadden: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Norah K. Judge: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Hannah E. Navarrete: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Britton C Michmerhuizen: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Dominik Awad: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Tracey L. Schultz: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Paul W. Harms: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Li Zhang: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Teresa R. O’Meara: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Jonathan Z. Sexton: Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Costas A. Lyssiotis: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
J. Michelle Kahlenberg: Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Mary X. O’Riordan: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 8
p. 114607

Abstract

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Summary: Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating metabolic and inflammatory programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. We find that staggered Toll-like receptor and type I IFN signaling in macrophages permit a transient energetic state of combined oxidative phosphorylation (OXPHOS) and aerobic glycolysis followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. This disruption promotes type I IFN, suppressing other pro-inflammatory cytokines, notably interleukin-1β. Upon infection, iNOS expression peaks at 24 h, followed by lactate-driven Nos2 repression via histone lactylation. Type I IFN pre-conditioning prolongs infection-induced iNOS expression, amplifying type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN results in elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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