Metabolic adaptations of inflammatory macrophages govern ferroptosis susceptibility via the GCH1–BH4–iNOS axis
Abstract
Abstract In inflammatory tissue niches, macrophages encounter intense oxidative stress due to their own production of reactive oxygen and nitrogen species as part of antimicrobial defense. Our findings reveal that inflammatory macrophages deploy distinct, context-dependent redox-protective mechanisms to survive this self-inflicted stress, thereby avoiding ferroptotic cell death. Specifically, LPS-activated macrophages, M(LPS), rely on the GTP cyclohydrolase 1 (GCH1)–tetrahydrobiopterin (BH4) pathway for ferroptosis resistance, whereas LPS + IFN-γ–activated macrophages, M(LPS–IFN-γ), depend primarily on nitric oxide produced by inducible nitric oxide synthase (iNOS)—with the BH4 pathway suppressing cell death in the absence of nitric oxide. These distinct adaptations highlight a novel GCH1–BH4–iNOS axis that governs macrophage ferroptosis susceptibility. In both the LPS or the LPS + IFN-γ–activated settings, the redox-protective phenotype is reversible: Removal of inflammatory stimuli abolishes the protection, indicating that this metabolic programming requires continuous stimulation and is not a permanently fixed state. These findings uncover redox metabolism-guided metabolic distinctions between inflammatory macrophages and reveal how they preserve viability over prolonged inflammatory activation. Ultimately, our findings establish the GCH1–BH4–iNOS axis as a central, targetable mechanism to manipulate macrophage ferroptosis resistance for therapeutic purposes.
Article Details
Journal Info
The Journal of Immunology
American Association of Immunologists
Authors (20)
Julia Sauer
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Patricia P Ogger
Department of Immunoregulation, Max Planck Institute of Biochemistry , Martinsried,
Jasmina Dukic
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Alina Nessensohn
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Svenja Gabler
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Ann-Katrin Schwenzer
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Julia Kirstin Unsöld
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Birgit Maria Cortès
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Barbara Steigenberger
Nuria Fernandez Perez
Department of Immunoregulation, Max Planck Institute of Biochemistry , Martinsried,
Alexander Strasser
Department of Immunoregulation, Max Planck Institute of Biochemistry , Martinsried,
Rodrigo Dias Requiao
Department of Immunoregulation, Max Planck Institute of Biochemistry , Martinsried,
Ulrike Schleicher
Mikrobiologisches Institut—Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen,
Eva Griesser
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Tom Bretschneider
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Florian Gantner
Matthew James Thomas
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Carolin Kirstin Watson
Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riß,
Karim Christian El Kasmi
Boehringer Ingelheim Pharma , Ridgefield, CT,
Peter J Murray
Department of Biology, Graduate School of Biological Sciences, University of Konstanz , Konstanz,