Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection
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.
Authors
- Britton C Michmerhuizen (ORCID: https://orcid.org/0009-0000-5997-9581)
- Jonathan Z. Sexton (ORCID: https://orcid.org/0000-0002-9244-5888)
- Mack B. Reynolds (ORCID: https://orcid.org/0000-0002-8445-3749)
- Tracey L. Schultz (ORCID: https://orcid.org/0009-0008-3133-8756)
- Benjamin Klein (ORCID: https://orcid.org/0000-0002-3412-5536)
- Paul W. Harms (ORCID: https://orcid.org/0000-0002-0802-2883)
- Teresa R. O’Meara (ORCID: https://orcid.org/0000-0002-8901-0154)
- Dominik Awad (ORCID: https://orcid.org/0000-0002-7386-2061)
- Michael J. McFadden (ORCID: https://orcid.org/0000-0003-0303-6968)
- Joanne Michelle Kahlenberg (ORCID: https://orcid.org/0000-0002-4006-8945)
- Mary O’Riordan (ORCID: https://orcid.org/0000-0001-6014-4637)
- Costas Andreas Lyssiotis (ORCID: https://orcid.org/0000-0001-9309-6141)
- Norah K. Judge (ORCID: https://orcid.org/0009-0005-6746-7494)
- Hannah E. Navarrete (ORCID: https://orcid.org/0000-0002-9147-9779)
- Li Zhang (ORCID: https://orcid.org/0000-0002-0703-7506)
Institutions
- University of Michigan (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114607
- Citations
- 19
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 4.57
Funders
- American Heart Association
- Barth Syndrome Foundation
- University of Michigan
- Janssen Scientific Affairs
- Nihon Kohden America
- Deutsche Forschungsgemeinschaft
- American Academy in Rome
- German-Israeli Foundation for Scientific Research and Development
- National Institutes of Health
- Rogel Cancer Center, University of Michigan
- National Cancer Institute