%0 Journal Article
%T Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.
%A Reynolds MB
%A Klein B
%A McFadden MJ
%A Judge NK
%A Navarrete HE
%A Michmerhuizen BC
%A Awad D
%A Schultz TL
%A Harms PW
%A Zhang L
%A O'Meara TR
%A Sexton JZ
%A Lyssiotis CA
%A Kahlenberg JM
%A O'Riordan MX
%J Cell Rep
%V 43
%N 8
%D 2024 Aug 27
%M 39126652
暂无%R 10.1016/j.celrep.2024.114607
%X 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.