Distinct metabolic responses to heme in inflammatory human and mouse macrophages – Role of nitric oxide
Pooja Pradhan,
Vijith Vijayan,
Bin Liu,
Beatriz Martinez-Delgado,
Nerea Matamala,
Christoph Nikolin,
Robert Greite,
David S. DeLuca,
Sabina Janciauskiene,
Roberto Motterlini,
Roberta Foresti,
Stephan Immenschuh
Affiliations
Pooja Pradhan
Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
Vijith Vijayan
Department of Pediatrics, Stanford University, Stanford, USA
Bin Liu
Department of Pulmonary and Infectious Diseases and BREATH German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
Beatriz Martinez-Delgado
Molecular Genetics and Genetic Diagnostic Units, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220, Madrid, Spain
Nerea Matamala
Molecular Genetics and Genetic Diagnostic Units, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220, Madrid, Spain
Christoph Nikolin
Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
Robert Greite
Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
David S. DeLuca
Department of Pulmonary and Infectious Diseases and BREATH German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
Sabina Janciauskiene
Department of Pulmonary and Infectious Diseases and BREATH German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
Roberto Motterlini
University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France
Roberta Foresti
University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France
Stephan Immenschuh
Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany; Corresponding author. Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School Carl-Neuberg-Str. 1, 30625, Hannover, Germany. [email protected]
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.
