Neutrophils are the most abundant leukocytes of blood and lymph circulation in mammals and the first ones of host's innate immune system to be recruited during acute inflammatory processes. This cell has unique oxidative effector mechanisms commanded by NADPH oxidase (NOX) and/or non-oxidative mechanisms through the release of granular contents which allows the release of antimicrobial peptides/proteins through degranulation, production of reactive oxygen species (ROS) which all efficiently contribute to the killing of invasive pathogens. However, during this killing process, there is also damage of tissues/organs, a situation that is more evident during inflammatory processes, not necessarily linked to infections, such as autoimmune or metabolic diseases.
One of the most recent effector mechanisms displayed by activated neutrophils is the release of extracellular neutrophil traps (NETs). This novel effector mechanism can be activated not only by various soluble stimuli but also by invasive microorganisms, such bacteria, viruses, fungi, protozoan and metazoan parasites as well as numerous pro-inflammatory agents.
Neutrophils have traditionally be considered as leukocytes with low transcriptional activities, but recent research in the field led to a twist in the dogma of neutrophil biology and has allowed supporting the existence of subpopulation heterogeneity, and critical functions for innate immunity and inflammation. Likewise, the recent development of metabolic plasticity in neutrophils has questioned the established concept of their exclusive dependence on the glycolytic pathway. Distinct metabolic adaptations and regulations are finely regulated and have been identified as critical to neutrophil differentiation and functions. The metabolic reprogramming of neutrophils by inflammatory mediators or during pathologies such as sepsis, diabetes, glucose-6-phosphate dehydrogenase deficiency, glycogen storage diseases (GSDs), systemic lupus erythematosus (SLE), rheumatoid arthritis, reproduction disorders, and cancer are now actively studied.
Recent studies challenge the pivotal role of glycolysis on neutrophil functions. Different metabolic pathways including the tricarboxylic acid cycle (TCA), also known as the Krebs cycle, oxidative phosphorylation (OXPHOS), the pentose phosphate pathway (PPP), fatty acid oxidation (FAO) are being recognized as necessary mechanisms to meet the energetic, biosynthetic and functional requirements of neutrophils. Evidence suggests that diverse metabolites produced for these metabolic pathways can modulate biology of neutrophils and exert relevant pro-inflammatory modulation in vivo. In fact, metabolic disorders can drastically affect the responses of pro-inflammatory agents or even the fight against microorganisms and large parasites by altering the metabolic pathways, which regulate the release of NETs. Despite having some novel insights supporting clear diverse role of neutrophil-derived metabolism on NETs extrusion, more research is needed to discover and understand this intriguing puzzle and contribute to novel drug targets in case of NETs-mediated metabolic disorders not only in human but also in domestic livestock.
Therefore, in this new Research Topic, we welcome the submission of Original Research, Review, Mini Review articles, which cover, but are not limited to the following subtopics:
1. The effect of metabolic ligands or metabolic receptors on NETs formation
2. How intracellular signaling is affected by changes in neutrophil metabolism during the formation of NETs
3. The role of metabolic disorders on NETs formation and innate immune response
4. The role of metabolic ligands or metabolic receptors in pathogen-triggered NETs release
5. Novel drug development hampering metabolic-derived NET formation
