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

• DOI: 10.1016/j.celrep.2024.114607
• Publication Date: 2024-08-09T10:10:47Z
• Authors: Mack B. Reynolds; Benjamin Klein; Michael J. McFadden; Norah K. Judge; Hannah E. Navarrete; Britton C Michmer...; Dominik Awad; Tracey L. Schultz; Paul W. Harms; Li Zhang; Teresa R. O’Meara; Jonathan Z. Sexton; Costas A. Lyssiotis; J. Michelle Kahle...; Mary X. O’Riordan
• Keywords: Methicillin-Resistant Staphylococcus aureus; 570; Staphylococcus aureus; QH301-705.5; immunometabolism; Interleukin-1beta; 610; Nitric Oxide Synthase Type II; macrophage; Inbred C57BL; Article; Oxidative Phosphorylation; Mice; 03 medical and health sciences; nitric oxide; Animals; Biology (General); innate immunity; Inflammation; lactate; 0303 health sciences; epigenetics; Macrophages; respiratory complex; CP: Immunology; interferon; Staphylococcal Infections; CP: Metabolism; Mice, Inbred C57BL; inflammation; Interferon Type I; Glycolysis; Signal Transduction

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