Regulatory interplay between nitric oxide and heme in redox signaling and inflammation

Nitric oxide (NO) is a key signaling gas that is involved in a wide range of physiological and pathophysiological processes. NO signaling is closely linked to its interactions with heme, an abundant iron-containing tetrapyrrole in the organism. While heme plays vital roles as a prosthetic group in hemoproteins, it can be toxic in its 'free', non-protein-bound form. The chemical and structural characteristics of NO-heme binding in heme-nitrosyl complexes have been extensively characterized in earlier research. Recent studies have provided novel insights on how NO-heme interactions affect key functions of the cell and activities of subcellular organelles such as mitochondria. Notably, the NO-heme network plays a crucial immunomodulatory role in inflammatory responses of macrophages, a major cell population of the innate immune system. Upon immunological activation, these cells generate large amounts of NO through activation of the inducible nitric oxide synthase (iNOS), which contributes to killing of bacteria and modulating of inflammation. NO generates microbicidal pro-oxidant peroxynitrite, which in turn activates feedback loops that provide autoprotection to macrophages. Interestingly, the dynamic interaction between NO and heme adds to the complex control of various heme-containing enzymes involved in inflammation and cellular oxidative stress adaptation. NO interacts with heme both directly and indirectly through multiple biochemical reactions, such as S-nitrosylation of cysteine residues and allocation of heme into specific hemoproteins. The current review summarizes key aspects of the regulatory interplay between NO and heme, highlighting its functional consequences in health and disease. A particular emphasis is on the significance of the NO-heme network in inflammation, especially its role in macrophages.