Exogenous glutamine impairs neutrophils migration into infections sites elicited by lipopolysaccharide by a multistep mechanism

Santos, Andressa Cristina Antunes; Hebeba, Cristina Bichels; Hastreiter, Araceli Aparecida; Oliveira, Dalila Cunha de; Makiyama, Edson Naoto; Farsky, Sandra Helena Poliselli; Borelli, Primavera; Fock, Ricardo Ambrósio

doi:10.1007/s00726-018-2679-3

Cited by 7 publications

(4 citation statements)

References 49 publications

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“…Ouwendijk et al suggested that regulated NETs formation may defend hosts against SARS-CoV-2 infection in asymptomatic or mild cases, but additional factors may lead to excessive NETs production and lung obstruction [ 25 ]. Comorbidity-associated glutamine deficiency may be one of the factors contributing to pathologic NETs production, as glutamine impaired the chemotactic migration of neutrophils to infection sites in an animal model [ 81 ], and glutamine deprivation induced the expression of IL-8 [ 82 , 83 ].…”

Section: Consequences Of Glutamine Deficiency and Covid-19mentioning

confidence: 99%

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

Matsuyama

Yoshinaga²,

Shibue

et al. 2021

Cell Death Differ

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SARS-CoV-2 vaccinations have greatly reduced COVID-19 cases, but we must continue to develop our understanding of the nature of the disease and its effects on human immunity. Previously, we suggested that a dysregulated STAT3 pathway following SARS-Co-2 infection ultimately leads to PAI-1 activation and cascades of pathologies. The major COVID-19-associated metabolic risks (old age, hypertension, cardiovascular diseases, diabetes, and obesity) share high PAI-1 levels and could predispose certain groups to severe COVID-19 complications. In this review article, we describe the common metabolic profile that is shared between all of these high-risk groups and COVID-19. This profile not only involves high levels of PAI-1 and STAT3 as previously described, but also includes low levels of glutamine and NAD + , coupled with overproduction of hyaluronan (HA). SARS-CoV-2 infection exacerbates this metabolic imbalance and predisposes these patients to the severe pathophysiologies of COVID-19, including the involvement of NETs (neutrophil extracellular traps) and HA overproduction in the lung. While hyperinflammation due to proinflammatory cytokine overproduction has been frequently documented, it is recently recognized that the immune response is markedly suppressed in some cases by the expansion and activity of MDSCs (myeloid-derived suppressor cells) and FoxP3 + Tregs (regulatory T cells). The metabolomics profiles of severe COVID-19 patients and patients with advanced cancer are similar, and in high-risk patients, SARS-CoV-2 infection leads to aberrant STAT3 activation, which promotes a cancer-like metabolism. We propose that glutamine deficiency and overproduced HA is the central metabolic characteristic of COVID-19 and its high-risk groups. We suggest the usage of glutamine supplementation and the repurposing of cancer drugs to prevent the development of severe COVID-19 pneumonia.

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Section: Consequences Of Glutamine Deficiency and Covid-19mentioning

confidence: 99%

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

Matsuyama

Yoshinaga²,

Shibue

et al. 2021

Cell Death Differ

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“…Another report describes the role of exogenous glutamine in neutrophils chemotaxis. The authors showed that glutamine administration impairs neutrophils migration during endotoxemia, induced by E. coli lipopolysaccharide (LPS) [112]. The migration of neutrophils was enhanced in the absence of glutamine, which suggests a drop in glutamine concentration during infection would facilitate neutrophils migration to inflammation sites.…”

Section: Neutrophils' Metabolic Shift From Plasma To Tissuesmentioning

confidence: 99%

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

Injarabian

Devin

Ransac

et al. 2019

IJMS

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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.

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“…In addition, glutamine exerts important effects on neutrophils. Glutamine protects neutrophils against apoptosis and impairs the chemotactic migration of neutrophils to sites of infection [61,62]. By blocking the secretion of interleukin-8, the amino acid may likewise prevent the release of neutrophil extracellular traps (NETosis), which combat SARS-CoV-2 infection but are linked to vessel occlusion and multiorgan damage in autopsied COVID-19 patients [63,64].…”

Section: Role Of Glutamine In Immune Cellsmentioning

confidence: 99%

Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19

Durante

2023

IJMS

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The coronavirus disease 2019 (COVID-19) pandemic has caused the death of almost 7 million people worldwide. While vaccinations and new antiviral drugs have greatly reduced the number of COVID-19 cases, there remains a need for additional therapeutic strategies to combat this deadly disease. Accumulating clinical data have discovered a deficiency of circulating glutamine in patients with COVID-19 that associates with disease severity. Glutamine is a semi-essential amino acid that is metabolized to a plethora of metabolites that serve as central modulators of immune and endothelial cell function. A majority of glutamine is metabolized to glutamate and ammonia by the mitochondrial enzyme glutaminase (GLS). Notably, GLS activity is upregulated in COVID-19, favoring the catabolism of glutamine. This disturbance in glutamine metabolism may provoke immune and endothelial cell dysfunction that contributes to the development of severe infection, inflammation, oxidative stress, vasospasm, and coagulopathy, which leads to vascular occlusion, multi-organ failure, and death. Strategies that restore the plasma concentration of glutamine, its metabolites, and/or its downstream effectors, in conjunction with antiviral drugs, represent a promising therapeutic approach that may restore immune and endothelial cell function and prevent the development of occlusive vascular disease in patients stricken with COVID-19.

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Exogenous glutamine impairs neutrophils migration into infections sites elicited by lipopolysaccharide by a multistep mechanism

Cited by 7 publications

References 49 publications

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

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

Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19

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