Bogdan concludes his recent review “Nitric oxide and the immune response” by stating: “the demonstration of iNOS expression by macrophages and other cell types in tissues from patients with a wide variety of infectious, autoimmune and degenerative diseases has disproved the claim that iNOS does not occur in the human immune system”1. The article provides the reader with a view with which we, investigators working with nonmurine macrophages, do not unequivocally agree.
Human macrophages are different from mouse and rat macrophages in their nitric oxide (NO) production, both in vitro and in vivo2,3,4,5,6. Mouse macrophages synthesize large amounts of NO from the substrate l-arginine, synthesize the obligate cofactor tetrahydrobiopterin (H4B) and use arginase as the main enzyme metabolizing l-arginine—enzyme systems not functional in human macrophages7,8. These pathways are present in all cell types that produce NO in vitro and in vivo, including human hepatocytes and human smooth muscle cells9,10.
The profound differences among species are not confined to human and mouse macrophages. Caprine, lapine and porcine macrophages also do not generate NO, whereas bovine macrophages do11. Fundamental species differences are common in immunology and other disciplines12,13.
None of the articles describing patient material that were cited by Bogdan specify the location and identity of the cell type responsible for NO synthesis1. Whenever a specific cell type is proposed to have inducible nitric oxide synthase (iNOS), or any type of enzyme activity, the questions of substrate (l-arginine) consumption, cosubstrate (l-citrulline) production and cofactor (H4B) availability or production have to be answered simultaneously. The cited articles do not address these issues. Documentation of the presence of mRNA or protein on its own is not proof of functional enzyme activity. Recently, Kun et al. described a point mutation in the iNOS promoter in Africans that correlates with protection against malaria14. It remains to be investigated whether the complete iNOS-H4B-arginase pathway is functional in purified macrophages from subjects carrying this mutation.
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Schneemann, M., Schoedon, G. Species differences in macrophage NO production are important. Nat Immunol 3, 102 (2002). https://doi.org/10.1038/ni0202-102a
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DOI: https://doi.org/10.1038/ni0202-102a
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