Type I interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression

Glennon‐Alty, Laurence; Moots, Robert J.; Edwards, Steven W.; Wright, Helen L.

doi:10.1111/cei.13525

Cited by 25 publications

(14 citation statements)

References 44 publications

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“…Further, HA- and TNFα-induced priming are synergistic, leading to an oxidative burst of even greater magnitude that ‘singly-primed’ neutrophils. Co-priming for the neutrophil oxidative burst has been reported previously for TNFα and IFNα ( 52 ), but this is the first evidence of neutrophil co-priming with a component of the ECM. The observed synergy between TNFα and HA priming may produce a ‘primed phenotype’ that is found in neutrophils at sites of tissue damage/inflammation where they are in contact with both HA and TNFα simultaneously.…”

Section: Discussionsupporting

confidence: 58%

Hyaluronan promotes intracellular ROS production and apoptosis in TNFα-stimulated neutrophils

Niemietz

Brown²

2023

Front. Immunol.

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BackgroundHyaluronan (HA) is an important structural component of the extracellular matrix and has well-described roles in maintaining tissue integrity and homeostasis. With inflammation, HA metabolism (synthesis and degradation) increases and results in higher concentrations of soluble HA. Previously, we demonstrated that (soluble) HA primed resting neutrophils for the oxidative burst in response to a secondary stimulus. Notably, HA-mediated priming was not dependent on degranulation, which is a hallmark of priming by classical agents such as TNFα. In this study, we queried the ability of HA to prime neutrophils to different stimuli and its capacity to modulate neutrophil function in the presence of TNFα.MethodsBlood neutrophils from healthy donors were stimulated ex vivo with HA in the absence and presence of classic neutrophil agonists, inclusive of TNFα. Western blotting was used to assess the activation (phosphorylation) of p38 MAPK, and key neutrophil functions associated with priming and activation, such as intracellular and extracellular ROS production, degranulation, and apoptosis, were evaluated by standard chemiluminescence assays (ROS) and flow cytometry.ResultsHyaluronan is capable of atypical priming and, with TNFα, co-priming neutrophils for an enhanced (rate and/or magnitude) oxidative burst to various secondary stimuli. In addition, HA can augment intracellular ROS production that is directly induced by TNFα in resting neutrophils, which coincided with the activation of p38 MAPK and apoptosis.ConclusionsThese data demonstrate that the extracellular matrix component HA is a key modulator of neutrophil function(s) in the presence of inflammatory agents such as TNFα. Moreover, it provides additional evidence for the diversity and complexity of neutrophil priming and activation during inflammation.

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Section: Discussionsupporting

confidence: 58%

Hyaluronan promotes intracellular ROS production and apoptosis in TNFα-stimulated neutrophils

Niemietz

Brown²

2023

Front. Immunol.

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“…711,712 Type I-IFNs, which were initially identified as having antiviral functions, have been found to possess a N1-promoting effect that opposes that of TGF-β. 713 Through the activation of various immune cells including neutrophils, T cells, NK cells, DCs, and macrophages, type I-IFNs showed potent anti-tumor function and inflammation regulation activities. 457 For instance, the deficiency of type I-IFN was shown to lead to a higher metastasis load with a massive accumulation of N2-TANs, which was characterized by the high expression of prometastatic proteins (e.g., S100A8, S100A9, VEGF, and MMP9), in the lungs of a premetastatic murine model.…”

Section: Adjusting the Inflammation In Innate Immunitymentioning

confidence: 99%

Inflammation and tumor progression: signaling pathways and targeted intervention

Zhao

Yan

et al. 2021

Sig Transduct Target Ther

1,120

682

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Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.

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“…However, there is now an increasing body of work demonstrating that neutrophil gene expression is dynamic, being rapidly regulated over short time points by exposure to inflammatory agents, such as TNFα, GM-CSF, IL-1β, LPS, and opsonized micro-particles (169)(170)(171), and over several hours by chromatin remodeling, for example in response to the TLR8 agonist resiquimod (R848) (172). Neutrophils have the capacity to express and secrete a wide range of inflammatory mediators, including interleukins (including IL-1α and−1β, IL-1RA, IL-6, IL-12, and IL-23), chemokines (CCL and CXCL family members), TNF superfamily members (including TNFα, BLyS/BAFF, APRIL, TRAIL, and RANKL), metabolites of arachidonic acid (leukotriene B4, prostaglandin E2, and thromboxane A2), and angiogenic factors, such as VEGF and HGF (8, 22, [173][174][175][176][177].…”

Section: Gene Expression and Cell Signallingmentioning

confidence: 99%

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

2021

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Dysregulated neutrophil activation contributes to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Neutrophil-derived reactive oxygen species (ROS) and granule proteases are implicated in damage to and destruction of host tissues in both conditions (cartilage in RA, vascular tissue in SLE) and also in the pathogenic post-translational modification of DNA and proteins. Neutrophil-derived cytokines and chemokines regulate both the innate and adaptive immune responses in RA and SLE, and neutrophil extracellular traps (NETs) expose nuclear neoepitopes (citrullinated proteins in RA, double-stranded DNA and nuclear proteins in SLE) to the immune system, initiating the production of auto-antibodies (ACPA in RA, anti-dsDNA and anti-acetylated/methylated histones in SLE). Neutrophil apoptosis is dysregulated in both conditions: in RA, delayed apoptosis within synovial joints contributes to chronic inflammation, immune cell recruitment and prolonged release of proteolytic enzymes, whereas in SLE enhanced apoptosis leads to increased apoptotic burden associated with development of anti-nuclear auto-antibodies. An unbalanced energy metabolism in SLE and RA neutrophils contributes to the pathology of both diseases; increased hypoxia and glycolysis in RA drives neutrophil activation and NET production, whereas decreased redox capacity increases ROS-mediated damage in SLE. Neutrophil low-density granulocytes (LDGs), present in high numbers in the blood of both RA and SLE patients, have opposing phenotypes contributing to clinical manifestations of each disease. In this review we will describe the complex and contrasting phenotype of neutrophils and LDGs in RA and SLE and discuss their discrete roles in the pathogenesis of each condition. We will also review our current understanding of transcriptomic and metabolomic regulation of neutrophil phenotype in RA and SLE and discuss opportunities for therapeutic targeting of neutrophil activation in inflammatory auto-immune disease.

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Type I interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression

Cited by 25 publications

References 44 publications

Hyaluronan promotes intracellular ROS production and apoptosis in TNFα-stimulated neutrophils

Hyaluronan promotes intracellular ROS production and apoptosis in TNFα-stimulated neutrophils

Inflammation and tumor progression: signaling pathways and targeted intervention

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

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