Neutrophil Metabolic Shift during Their Lifecycle: Impact on Their Survival and Activation

Abstract

Polymorphonuclear neutrophils (PMNs) are innate immune cells, which represent 50% to 70% of the total circulating leukocytes. How PMNs adapt to various microenvironments encountered during their life cycle, from the bone marrow, to the blood plasma fraction, and to inflamed or infected tissues remains largely unexplored. Metabolic shifts have been reported in other immune cells such as macrophages or lymphocytes, in response to local changes in their microenvironment, and in association with a modulation of their pro-inflammatory or anti-inflammatory functions. The potential contribution of metabolic shifts in the modulation of neutrophil activation or survival is anticipated even though it is not yet fully described. If neutrophils are considered to be mainly glycolytic, the relative importance of alternative metabolic pathways, such as the pentose phosphate pathway, glutaminolysis, or the mitochondrial oxidative metabolism, has not been fully considered during activation. This statement may be explained by the lack of knowledge regarding the local availability of key metabolites such as glucose, glutamine, and substrates, such as oxygen from the bone marrow to inflamed tissues. As highlighted in this review, the link between specific metabolic pathways and neutrophil activation has been outlined in many reports. However, the impact of neutrophil activation on metabolic shifts’ induction has not yet been explored. Beyond its importance in neutrophil survival capacity in response to available metabolites, metabolic shifts may also contribute to neutrophil population heterogeneity reported in cancer (tumor-associated neutrophil) or auto-immune diseases (Low/High Density Neutrophils). This represents an active field of research. In conclusion, the characterization of neutrophil metabolic shifts is an emerging field that may provide important knowledge on neutrophil physiology and activation modulation. The related question of microenvironmental changes occurring during inflammation, to which neutrophils will respond to, will have to be addressed to fully appreciate the importance of neutrophil metabolic shifts in inflammatory diseases.

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

“…At this point α-ketoglutarate enters the TCA cycle and is converted to malate which is then transported out of the mitochondria to be converted into pyruvate, which just like in glucose metabolism is converted into lactate to generate NAD + ( 234 , 237 ). Under conditions when glucose supply is limited, neutrophils can switch to the utilization of glutamine to meet their energetic needs ( 238 ). Furthermore, glutamine addition to cell culture medium of isolated neutrophils increases their phagocytic activity and rate of superoxide production ( 239 ).…”

Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer

“…Conversely, lactate accumulation in the TME has been shown to directly inhibit CTC immune function, as well as promote MDSC activation and the consequent suppression of T cells [ 80 , 81 ]. The glycolytic shift has also been observed to promote neutrophil activation and NET formation, and macrophage polarization and their inflammatory activity is thought to be regulated largely by TCA intermediates, such as succinate downstream of glycolytic reprogramming [ 82 , 83 ]. Taken together, it is indeed likely that metformin exerts its beneficial effects on an immune-reactive TME, at least in part, through its promotion of glycolytic activity.…”

Neutrophil in Reverse Migration: Role in Sepsis

“…The infiltration of PMNs from circulation to an inflammatory site is a regulated multi-stage process, as summarized in several review articles ( 2 , 6 , 22 ). PMNs first recognize inflammatory signs by sensing chemokines, e.g., macrophage-inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC) ( 23 , 24 ), followed by several processes, including capture, rolling, firm adhesion, and transendothelial migration, to reach the site of inflammation ( 25 , 26 ).…”

“…In the inflammatory site, PMNs eliminate pathogen through degranulation, phagocytosis, the formation of neutrophil extracellular traps (NETs), and releasing cytokines ( 3 , 4 ). After PMNs execute their antimicrobial agenda, timely clearance of PMNs is crucial to maintain homeostasis ( 2 , 5 , 6 ). Traditionally, apoptosis or necrosis and subsequent phagocytosis by macrophages were considered as the main ways for PMN clearance ( 7 , 8 ).…”