Inducible nitric oxide synthase: An asset to neutrophils

Abstract

Neutrophils play a key role in innate immune responses against foreign intrusion and influence the subsequent instigation of adaptive immune response. Nitric oxide (NO) synthesized by neutrophil nitric oxide synthase (NOS) profoundly modulates their diverse physiological responsibilities furthermore encompassing pathological implications. Neutrophils are the active participants in diverse inflammatory and cardiovascular disorders but neutrophil nitric oxide synthase (NOS) remains enigmatic on various aspects. This review focuses on inducible NOS (iNOS) and makes an attempt to address its potential impact in neutrophil pathophysiology, their differentiation, functionality, and survival. We described the scenario from its expressional modulation, by pro-and anti-inflammatory cytokines governing the extent and duration of neutrophil immune response, to iNOS catalysis, the intracellular compartmentalization, and protein-protein interactions determining its microenvironment, activity and its contribution as a potential signaling protein apart from its role as signal transducer. Further, the relevance of investigating the unexplored facets of iNOS biology in neutrophils and possible prototypes of iNOS regulation is also exemplified in related cellular systems. K E Y W O R D Sinducible nitric oxide synthase, neutrophils, protein interaction, regulation, subcellular localization INTRODUCTIONSince its discovery as endothelium-derived growth factor, NO has been related to a broad spectrum of signaling pathways in diverse pathophysiological, immunomodulatory, 1-3 and pharmacological responses.NO regulates functional attributes of neutrophils modulating their chemotactic, phagocytic, migratory, and apoptotic activities 4 as elaborated in Fig. 1. Neutrophils generate NO at a rate of (10-100) nmoles /5 min/10 6 cells. 5 These comprise 60-70% of the total peripheral leukocytes in humans, contribute significantly to the circulating levels, encompassing a widespread impact on cardiovascular homeostasis.Being capable against invading pathogens, a tumor cell, and alloantigens, NO is an asset to these immunocompetent cells, adding more to their cytotoxic battalion. It has also been demonstrated that NO mediates neutrophil extracellular traps (NET) release at the site of Abbreviations: AL, arginosuccinate lyase; AS, arginosuccinate synthase; Asc, ascorbate; BH 4 , tetrahydrobioptein; CaM, calmodulim; CGD, chronic granulomatous disease; DHA, dehydroascorbate; ETC, electron transport chain; Hsp, heat shock protein; I B, inhibitor kappa B; NLS, nuclear localization signal; PDZ, PSD-95/Disc large/ZO-1; PKC, protein kinase C; RNI, reactive nitrogen intermediates; ROCK, Rho-associated coiled coil containing protein kinase; TGF, tumor growth factor inflammation / infection by augmenting free radical generation. 6 Study by Napimoga et al. 7 depicted that peroxisome proliferator-activated receptor-(PPAR-) reduces neutrophil migration to the acute inflammatory mesenteric lesion as a result of reduction of rolling and adhesion activities of neu...

Neutrophils suppress mucosal‐associated invariant T cells in humans

“…A previous report found arginine supplementation had no effect on neutrophil suppression of γδ T cells, though this was assessed using only one activation marker, CD25, and the experimental setup differed to this study . In addition to arginase activity, neutrophils are able to rapidly deplete exogenous arginine through importation and nitric oxide synthase (NOS) mediated metabolism to nitric oxide and citrulline . Future experiments should examine the effect of blocking NOS activity alone, as well as in combination with arginase inhibition, as these enzymes are known to compete for arginine .…”

Neutrophils Suppress Mucosal-Associated Invariant T Cells

“…19 In addition to arginase activity, neutrophils are able to rapidly deplete exogenous arginine through importation and nitric oxide synthase (NOS) mediated metabolism to nitric oxide (NO) and citrulline. 39 Future experiments should examine the effect of blocking NOS activity alone, as well as in combination with arginase inhibition, as these enzymes are known to compete for arginine. 40…”

Bioinorganics and Wound Healing

“…NO inhibition significantly enhances neutrophils chemotaxis in a dose‐dependent manner and downregulate neutrophils' recruitment . NO reduces neutrophil adhesion to endothelial cell;231a it plays a key role during the respiratory burst as a messenger and as a reactive specie; it regulates as well their apoptosis through caspase 8 cleavage and caspase 9 activation that are enhanced in the presence of NO . Similarly, macrophages are capable of sustaining and high NO release initiated by inflammatory cytokines for a cytostatic or cytotoxic purpose against bacteria, fungi, tumor cells, etc .…”