2026-06-14T03:36:19Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/250712025-12-18T12:59:17Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616
Repisalud
author
Pradhan, Pooja
author
Vijayan, Vijith
author
Liu, Bin
author
Martinez-Delgado, Beatriz
author
Matamala, Nerea
author
Nikolin, Christoph
author
Greite, Robert
author
DeLuca, David S
author
Janciauskiene, Sabina
author
Motterlini, Roberto
author
Foresti, Roberta
author
Immenschuh, Stephan
funder
Deutsche Forschungsgemeinschaft (Alemania)
funder
Unión Europea
funder
Féderation Française de Cardiologie
2024-10-09T10:49:54Z
2024-10-09T10:49:54Z
2024-07
Redox Biol. 2024 Jul:73:103191.
10.1016/j.redox.2024.103191
2213-2317
2213-2317
Redox biology
38762951
https://hdl.handle.net/20.500.12105/25071
Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and pro-inflammatory effects in murine macrophages, but has been associated with polarization towards an anti-inflammatory phenotype in human macrophages. In the current study, we compared the regulatory responses to heme and the prototypical Toll-like receptor (TLR)4 ligand lipopolysaccharide (LPS) in human and mouse macrophages with a particular focus on alterations of cellular bioenergetics. In human macrophages, bulk RNA-sequencing analysis indicated that heme led to an anti-inflammatory transcriptional profile, whereas LPS induced a classical pro-inflammatory gene response. Co-stimulation of heme with LPS caused opposing regulatory patterns of inflammatory activation and cellular bioenergetics in human and mouse macrophages. Specifically, in LPS-stimulated murine, but not human macrophages, heme led to a marked suppression of oxidative phosphorylation and an up-regulation of glycolysis. The species-specific alterations in cellular bioenergetics and inflammatory responses to heme were critically dependent on the availability of nitric oxide (NO) that is generated in inflammatory mouse, but not human macrophages. Accordingly, studies with an inducible nitric oxide synthase (iNOS) inhibitor in mouse, and a pharmacological NO donor in human macrophages, reveal that NO is responsible for the opposing effects of heme in these cells. Taken together, the current findings indicate that NO is critical for the immunomodulatory role of heme in macrophages.
eng
Heme
Inflammation
Lipopolysaccharide
Macrophages
Mitochondrial metabolism
Nitric oxide
Distinct metabolic responses to heme in inflammatory human and mouse macrophages - Role of nitric oxide
research article
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