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 (O2•−) 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 O2•− 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.