The Critical Role of Cell Metabolism for Essential Neutrophil Functions

Curi, Rui; Levada‐Pires, Adriana Cristina; Silva, Eliane Borges da; Poma, Sarah de Oliveira; Zambonatto, Raquel Freitas; Domenech, Paola; Almeida, Mariana Mendes de; Gritte, Raquel Bragante; Souza‐Siqueira, Talita; Gorjão, Renata; Newsholme, Philip; Pithon-Curi, Tânia Cristina

doi:10.33594/000000245

Cited by 65 publications

(50 citation statements)

References 126 publications

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“…Neutrophils exhibit a remarkable metabolic plasticity allowing them to survive in extremes of metabolite availability and contributing toward neutrophil population heterogeneity described in cancer-associated neutrophils and in density-gradient isolated low and high buoyancy neutrophils seen in auto-immune diseases ( 100 ). The metabolic reconfiguration of neutrophils effected by mediators released during chronic inflammatory states and carcinogenesis is an area of intense investigation and research ( 101 ).…”

Section: Neutrophil Biologymentioning

confidence: 99%

Neutrophil NETworking in ENL: Potential as a Putative Biomarker: Future Insights

Sahu

Sharma

et al. 2021

Front. Med.

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Erythema nodosum leprosum (ENL), also known as type 2 reaction (T2R) is an immune complex mediated (type III hypersensitivity) reactional state encountered in patients with borderline lepromatous and lepromatous leprosy (BL and LL) either before, during, or after the institution of anti-leprosy treatment (ALT). The consequences of ENL may be serious, leading to permanent nerve damage and deformities, constituting a major cause of leprosy-related morbidity. The incidence of ENL is increasing with the increasing number of multibacillary cases. Although the diagnosis of ENL is not difficult to make for physicians involved in the care of leprosy patients, its management continues to be a most challenging aspect of the leprosy eradication program: the chronic and recurrent painful skin lesions, neuritis, and organ involvement necessitates prolonged treatment with prednisolone, thalidomide, and anti-inflammatory and immunosuppressive drugs, which further adds to the existing morbidity. In addition, the use of immunosuppressants like methotrexate, azathioprine, cyclosporine, or biologics carries a risk of reactivation of persisters (Mycobacterium leprae), apart from their own end-organ toxicities. Most ENL therapeutic guidelines are primarily designed for acute episodes and there is scarcity of literature on management of patients with chronic and recurrent ENL. It is difficult to predict which patients will develop chronic or recurrent ENL and plan the treatment accordingly. We need simple point-of-care or ELISA-based tests from blood or skin biopsy samples, which can help us in identifying patients who are likely to require prolonged treatment and also inform us about the prognosis of reactions so that appropriate therapy may be started and continued for better ENL control in such patients. There is a significant unmet need for research for better understanding the immunopathogenesis of, and biomarkers for, ENL to improve clinical stratification and therapeutics. In this review we will discuss the potential of neutrophils (polymorphonuclear granulocytes) as putative diagnostic and prognostic biomarkers by virtue of their universal abundance in human blood, functional versatility, phenotypic heterogeneity, metabolic plasticity, differential hierarchical cytoplasmic granule mobilization, and their ability to form NETs (neutrophil extracellular traps). We will touch upon the various aspects of neutrophil biology relevant to ENL pathophysiology in a step-wise manner. We also hypothesize about an element of metabolic reprogramming of neutrophils by M. leprae that could be investigated and exploited for biomarker discovery. In the end, a potential role for neutrophil derived exosomes as a novel biomarker for ENL will also be explored.

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Section: Neutrophil Biologymentioning

confidence: 99%

Neutrophil NETworking in ENL: Potential as a Putative Biomarker: Future Insights

Sahu

Sharma

et al. 2021

Front. Med.

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“…There is now very clear scientific evidence, defining the metabolic and signalling pathways underlying functional neutrophils 24 and those subjected to C5a-induced dysfunction 12,13,20,25 . Thus, ligation of C5aR1 (CD88) by C5a, activates its inherent G-protein activity resulting in phosphoinositide 3-kinase delta (PI3Kδ) activation inhibiting activation of the small GTPase RhoA, actin polymerisation and phagocytosis 13 .…”

Section: Discussionmentioning

confidence: 99%

Contrasting effects of linezolid on healthy and dysfunctional human neutrophils: reducing C5a-induced injury

Evans

Roberts

Morris

et al. 2020

Sci Rep

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Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of ventilator-associated pneumonia (VAP). Patients with VAP have poorly functioning neutrophils, related to increased levels of the complement fragment C5a. The antibiotic linezolid has been useful in controlling MRSA-related VAP infections; however clinical benefit does not always correlate with antimicrobial effect, suggesting the possibility of immunomodulatory properties. Here the effects of linezolid on healthy and dysfunctional neutrophils (modelled by C5a-induced injury) was investigated. Functional assays (killing, phagocytosis, transmigration, and respiratory burst) were used to assess the effects of pre-, co- and post-incubating linezolid (0.4–40 mg/L) with healthy neutrophils relative to those with C5a-induced injury. C5a decreased neutrophil killing, and phagocytosis of MRSA. Furthermore, C5a significantly decreased neutrophil transmigration to IL-8, but did not affect respiratory burst. Co-incubation of linezolid significantly improved killing of MRSA by dysfunctional neutrophils, which was supported by concomitant increases in phagocytosis. Conversely linezolid impaired killing responses in healthy neutrophils. Pre- or post-incubation of linezolid prior or following C5a induced injury had no effect on neutrophil function. This study suggests that linezolid has immunomodulatory properties that protect human neutrophils from injury and provides insight into its mode of action beyond a basic antibiotic.

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“…Upon stimulation by pathogen-derived molecules and endogenous ligands, immune cells undergo metabolic reprogramming into alternative modes of energy metabolism ( O’Neill et al, 2016 ; Gaber et al, 2017 ; Hotamisligil, 2017 ; Próchnicki and Latz, 2017 ), which can be largely classified into the pro-inflammatory phenotypes dominated by glycolysis (similar to the Warburg effect in cancer cells), and anti-inflammatory phenotypes characterized by TCA cycle, fatty acid oxidation, and OXPHOS ( O’Neill et al, 2016 ). Such bioenergetic shifts determine the properties of various immune cell populations, including macrophages ( Van den Bossche et al, 2017 ), neutrophils ( Curi et al, 2020 ), and T cells ( O’Neill et al, 2016 ; Spadaro et al, 2017 ; Balyan et al, 2020 ), where insulin/IGFs and leptin come into play. For example, insulin regulates T cell’s metabolic reprogramming, thereby shaping adaptive immunity ( Tsai et al, 2018 ).…”

Section: Metabolic Disturbance and Cognitive Impairmentmentioning

confidence: 99%

Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia

Shinjyo

Kita

2021

Front. Cell. Neurosci.

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Metabolic syndromes are frequently associated with dementia, suggesting that the dysregulation of energy metabolism can increase the risk of neurodegeneration and cognitive impairment. In addition, growing evidence suggests the link between infections and brain disorders, including Alzheimer’s disease. The immune system and energy metabolism are in an intricate relationship. Infection triggers immune responses, which are accompanied by imbalance in cellular and organismal energy metabolism, while metabolic disorders can lead to immune dysregulation and higher infection susceptibility. In the brain, the activities of brain-resident immune cells, including microglia, are associated with their metabolic signatures, which may be affected by central nervous system (CNS) infection. Conversely, metabolic dysregulation can compromise innate immunity in the brain, leading to enhanced CNS infection susceptibility. Thus, infection and metabolic imbalance can be intertwined to each other in the etiology of brain disorders, including dementia. Insulin and leptin play pivotal roles in the regulation of immunometabolism in the CNS and periphery, and dysfunction of these signaling pathways are associated with cognitive impairment. Meanwhile, infectious complications are often comorbid with diabetes and obesity, which are characterized by insulin resistance and leptin signaling deficiency. Examples include human immunodeficiency virus (HIV) infection and periodontal disease caused by an oral pathogen Porphyromonas gingivalis. This review explores potential interactions between infectious agents and insulin and leptin signaling pathways, and discuss possible mechanisms underlying the relationship between infection, metabolic dysregulation, and brain disorders, particularly focusing on the roles of insulin and leptin.

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The Critical Role of Cell Metabolism for Essential Neutrophil Functions

Cited by 65 publications

References 126 publications

Neutrophil NETworking in ENL: Potential as a Putative Biomarker: Future Insights

Neutrophil NETworking in ENL: Potential as a Putative Biomarker: Future Insights

Contrasting effects of linezolid on healthy and dysfunctional human neutrophils: reducing C5a-induced injury

Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia

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