The emerging role for metabolism in fueling neutrophilic inflammation

Morrison, Tyler; Watts, Emily R.; Sadiku, Pranvera; Walmsley, Sarah R.

doi:10.1111/imr.13157

Cited by 26 publications

(13 citation statements)

References 142 publications

(304 reference statements)

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“…Despite the low frequency of infection, RSV induced a similar inflammatory response as seen with other respiratory viruses, such as SARS-CoV-2 and IAV, with clear evidence of leukocyte recruitment and monocyte and T cell driven vasculitis and perivascular/peribronchial infiltration 84 . Daprodustat treatment dampened these inflammatory responses, although the recruitment of neutrophils was maintained, in line with earlier reports on hypoxia driving neutrophilic inflammation 85 . Preliminary experiments in mice infected with the genetically related pneumovirus of mice (PVM), a natural pathogen of rodents, support our findings with hRSV and showed a reduced frequency of infected cells and a less intense inflammatory response following Daprodustat treatment.…”

Section: Discussionsupporting

confidence: 91%

Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression

Zhuang,

Gallo,

Sharma

et al. 2023

Preprint

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Respiratory syncytial virus (RSV) is a global healthcare problem, causing respiratory illness in young children and elderly individuals. However, our knowledge of the host pathways that define susceptibility to RSV infection and disease severity is limited. Hypoxia inducible factors (HIFs) define cellular metabolic processes in response to low oxygen and are recognised to play a key role in regulating inflammatory responses in the lower respiratory tract. We demonstrate a role for hypoxia inducible factors (HIFs) to suppress RSV entry and RNA replication. We show that hypoxia and HIF prolyl-hydroxylase inhibitors significantly reduce expression of the RSV entry receptor nucleolin and inhibit viral driven cell-cell fusion. We identify a HIF regulated microRNA, miR-494, that regulates nucleolin expression. In RSV-infected mice, treatment with the clinically approved HIF prolyl-hydroxylase inhibitor, Daprodustat, reduced the level of infectious virus and infiltrating monocytes and neutrophils in the lung. This study highlights a role for HIF-signalling to limit multiple aspects of RSV infection and associated inflammation and informs future therapeutic approaches for treating this respiratory pathogen.

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Section: Discussionsupporting

confidence: 91%

Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression

Zhuang,

Gallo,

Sharma

et al. 2023

Preprint

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“…Despite recent advances in the field of immunometabolism, our understanding of neutrophil metabolism remains incomplete. Previous studies have indicated that neutrophils primarily rely on glucose as their primary carbon source for metabolic processes [40]. However, emerging evidence suggests that neutrophils also utilize a variety of other nutrients, including amino acids, carbohydrates, proteins, and lipids, to generate energy [41,42].…”

Section: Discussionmentioning

confidence: 99%

Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis

Sankar,

Ramos,

Corro

et al. 2023

Preprint

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Mycobacterium tuberculosis(Mtb) infection triggers a significant influx of neutrophils to the lungs, which is linked to tuberculosis (TB) severity. The mechanism by which Mtb infection induces neutrophillic inflammation remains unclear. Using a clinically relevant and hypervirulent Mtb strain from the W-Beijing family, HN878, we found that genes related to both glycolysis and fatty acid metabolism are upregulated in the lung neutrophils of susceptible mice. Similar effects in gene expression were observed in rabbits, and humans with pulmonary TB compared to healthy controls. Inhibiting glycolysis with 2-deoxy D-glucose (2-DG) exacerbated disease pathology, while fatty acid oxidation (FAO) inhibitor Etomoxir (ETO) improved outcomes by reducing weight loss, immunopathology, and bacterial replication within neutrophils in genetically susceptible mice. Notably, ETO reduced neutrophil production in the bone marrow and their recruitment to the lungs. ETO specifically restrained the recruitment of Ly6Glow/dimimmature neutrophil population, which is elevated during disease progression and harbors the bulk of bacilli. In a transwell setup, we demonstrated that ETO dose-dependently inhibited neutrophil chemotaxis towards infected macrophages. In summary, our research highlights the crucial role of fatty acid metabolism in regulating neutrophilic inflammation during TB and provides a rationale for targeting immunometabolism of neutrophils for potential TB treatment.

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“…The Warburg effect has already been described for activated macrophages [81], in trained monocytes [82], in monocyte-derived dendritic cells [83], in neutrophilic inflammation [84], and activated lymphocytes [85]. The main regulating factors driving this metabolic reprogramming from oxidative phosphorylation to fermentative glycolysis are hypoxia inducible factor (HIF)-1α and lactate.…”

Section: Introductionmentioning

confidence: 95%

Stress hyperglycaemia following trauma – a survival benefit or an outcome detriment?

Rugg,

Schmid,

Zipperle

et al. 2024

Current Opinion in Anaesthesiology

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Purpose of review Stress hyperglycaemia occur often in critically injured patients. To gain new consideration about it, this review compile current as well as known immunological and biochemical findings about causes and emergence. Recent findings Glucose is the preferred energy substrate for fending immune cells, reparative tissue and the cardiovascular system following trauma. To fulfil these energy needs, the liver is metabolically reprogrammed to rebuild glucose from lactate and glucogenic amino acids (hepatic insulin resistance) at the expenses of muscles mass and – to a less extent – fat tissue (proteolysis, lipolysis, peripheral insulin resistance). This inevitably leads to stress hyperglycaemia, which is evolutionary preserved and seems to be an essential and beneficial survival response. It is initiated by damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), intensified by immune cells itself and mainly ruled by tumour necrosis factor (TNF)α and catecholamines with lactate and hypoxia inducible factor (HIF)-1α as intracellular signals and lactate as an energy shuttle. Important biochemical mechanisms involved in this response are the Warburg effect as an efficient metabolic shortcut and the extended Cori cycle. Summary Stress hyperglycaemia is beneficial in an acute life-threatening situation, but further research is necessary, to prevent trauma patients from the detrimental effects of persisting hyperglycaemia.

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The emerging role for metabolism in fueling neutrophilic inflammation

Cited by 26 publications

References 142 publications

Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression

Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression

Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis

Stress hyperglycaemia following trauma – a survival benefit or an outcome detriment?

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