Nitric Oxide: Regulation and Function in Neutrophil Immune Responses.

Significance: Neutrophils are crucial components of the innate immune system that combat invading pathogens and maintain homeostasis. Nitric oxide (NO • ) exerts regulatory influence on neutrophil rolling, adhesion, oxidative burst, chemotaxis, phagocytosis, cytoneme, apoptosis, and NETosis by diverse mechanisms in an autocrine and paracrine manner. Recent Advances: Recent research has identified the critical role of NO • in the proliferation of neutrophil progenitors, differentiation, survival, and other functions. Further, NO • responses depend on the concentration, proximity, and redox environment, highlighting the intricate and context-dependent mechanisms by which NO • influences neutrophil responses. Critical Issues: Neutrophils express two constitutive isoforms of nitric oxide synthase (NOS), namely iNOS and nNOS. The production of NO • or superoxide (O 2 •- ) radical by these isoforms depends on levels of substrates L-arginine and oxygen, and cofactors such as NADPH, FAD, FMN, and redox-sensitive BH4. Importantly, the interaction between NO • and superoxide generates potent oxidants within the phagolysosomes. The coordinated collaboration and regulation of NO • and O 2 •- are crucial for redox signaling and neutrophil properties. Future Directions: The activity of neutrophil NOS is regulated at multiple levels, including transcriptional regulation, cofactor availability, protein-protein interactions, and post-translational modifications. However, our understanding of regulatory mechanisms during various neutrophil functions remains limited. While we now recognize the neutrophil heterogeneity, metabolic adaptability, and anti-tumoral ability; however, reports identifying NOS/NO • role remain largely unexplored on these aspects in infections, inflammation, and immunosuppression. Future studies addressing these intriguing areas will be crucial in unraveling the role of NO • /NOS signaling in neutrophils across diverse pathologies and may present therapeutic opportunities.