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
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.
