Glycolysis dependent lactate formation in neutrophils: A metabolic link between NOX-dependent and independent NETosis

Awasthi, Deepika; Nagarkoti, Sheela; Sadaf, Samreen; Chandra, Tulika; Kumar, Sachin; Dikshit, Madhu

doi:10.1016/j.bbadis.2019.165542

Cited by 82 publications

(72 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Importantly, elevated lactate levels coinciding with the rise of neutrophils in the circulation and inflamed tissues are associated with pathological conditions including shock, sepsis, and ischemia 62 . Lactate was also found to be released by human neutrophils 12 and it was shown that glucose uptake, enhanced glycolysis and lactate promoted neutrophil functions like phagocytic activity 63 and neutrophil extracellular traps formation 64 , 65 . However, how neutrophils produce lactate, and how this metabolite affects neutrophil function and mobilization during acute inflammation have been open questions.…”

Section: Discussionmentioning

confidence: 99%

Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling

et al. 2020

View full text Add to dashboard Cite

Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidasemediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81 −/− mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection.

show abstract

Section: Discussionmentioning

confidence: 99%

Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Regulated metabolism not only dictates the health of parenchymal tissues but underpins immune cell homeostasis (44,45). Granulocytes have few mitochondria and do not consume oxygen to any great extent; instead, they generate ATP for energy by aerobic glycolysis (lactate production) even in states of normoxia (the Warburg effect) (46). Macrophages, dendritic cells and T cells in quiescence generate ATP for energy requirements by oxidative phosphorylation (OXPHOS) but switch to aerobic glycolysis when activated (47).…”

Section: Is Inflammation In Diabetes a Direct Or An Indirect Cause Ofmentioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

View full text Add to dashboard Cite

Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5 + CD11b + monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.

show abstract

“…Significant changes in the lactate level during diverse metabolic and inflammatory diseases, like diabetes, sepsis etc, might modulate neutrophil responses and NETosis. Recent study conducted in our lab has demonstrated that lactate was formed during PMA and A23187 induced NETosis, and oxamate, a LDH inhibitor reduced NETs release by these mediators (81). Moreover, previous study from our lab has also demonstrated that oxidized LDL though TLR pathway induced NETosis in human PMNs (82), suggesting a possible role of FAO in NETosis and neutrophil-mediated tissue damage.…”

Section: Metabolic Regulation Of Neutrophil Functionsmentioning

confidence: 99%

Metabolic Insight of Neutrophils in Health and Disease

2019

Self Cite

View full text Add to dashboard Cite

Neutrophils are the most abundant, short lived, and terminally differentiated leukocytes with distinct tiers of arsenals to counter pathogens. Neutrophils were traditionally considered transcriptionally inactive cells, but recent researches in the field led to a paradigm shift in neutrophil biology and revealed subpopulation heterogeneity, and functions pivotal to immunity and inflammation. Furthermore, recent unfolding of metabolic plasticity in neutrophils has challenged the long-standing concept of their sole dependence on glycolytic pathway. Metabolic adaptations and distinct regulations have been identified which are critical for 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, and cancer are now being explored. In this review, we discuss recent developments in understanding of the metabolic regulation, that may provide clues for better management and newer therapeutic opportunities for neutrophil centric immuno-deficiencies and inflammatory disorders.

show abstract

Glycolysis dependent lactate formation in neutrophils: A metabolic link between NOX-dependent and independent NETosis

Cited by 82 publications

References 82 publications

Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling

Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling

The Role of Inflammation in Diabetic Retinopathy

Metabolic Insight of Neutrophils in Health and Disease

Contact Info

Product

Resources

About