The Role of TRAIL/DRs in the Modulation of Immune Cells and Responses

Sağ, Duygu; Ayyildiz, Zeynep Ozge; Gunalp, Sinem; Wingender, Gerhard

doi:10.3390/cancers11101469

Cited by 45 publications

(44 citation statements)

References 331 publications

(752 reference statements)

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“…An interesting aspect of TRAIL is its involvement in the homeostatic regulation of the immune system, as in fact, it is expressed on various innate and adaptive immune cell types [98], including monocytes, macrophages, natural killer cells, natural killer T cells, dendritic cells, and neutrophils after stimulation with lipopolysaccharide and pro-inflammatory cytokines such as IFNα, IFNβ, and IFNγ, as well as on T lymphocytes following T cell receptor (TCR)-mediated activation [99][100][101][102][103][104]. In contrast to the ligand, TRAIL-receptors are ubiquitously expressed also outside the immune system [105], and, for this reason, TRAIL seems to substantially modulate both the immune responses and their cellular components via the apoptotic cell-death pathway [106], and to participate to the immune response in different tissues and conditions [107][108][109][110].…”

Section: The Impact Of Central and Peripheral Inflammatory/ Immune Rementioning

confidence: 99%

The immune system on the TRAIL of Alzheimer’s disease

Burgaletto

Munafò

Benedetto

et al. 2020

J Neuroinflammation

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Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive degeneration and loss of neurons in specific regions of the central nervous system. Chronic activation of the immune cells resident in the brain, peripheral immune cell trafficking across the blood-brain barrier, and release of inflammatory and neurotoxic factors, appear critical contributors of the neuroinflammatory response that drives the progression of neurodegenerative processes in AD. As the neuro-immune network is impaired in course of AD, this review is aimed to point out the essential supportive role of innate and adaptive immune response either in normal brain as well as in brain recovery from injury. Since a fine-tuning of the immune response appears crucial to ensure proper nervous system functioning, we focused on the role of the TNF superfamily member, TNF-related apoptosis-inducing ligand (TRAIL), which modulates both the innate and adaptive immune response in the pathogenesis of several immunological disorders and, in particular, in AD-related neuroinflammation. We here summarized mounting evidence of potential involvement of TRAIL signaling in AD pathogenesis, with the aim to provide clearer insights about potential novel therapeutic approaches in AD.

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Section: The Impact Of Central and Peripheral Inflammatory/ Immune Rementioning

confidence: 99%

The immune system on the TRAIL of Alzheimer’s disease

Burgaletto

Munafò

Benedetto

et al. 2020

J Neuroinflammation

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“…In addition, because TRAIL provides an external trigger for apoptosis, it has the potential to overcome resistance to internal triggers of apoptosis after radiation or chemotherapy. There have been many excellent reviews on TRAIL biology and the mechanism of action with implication for therapeutic applications in recent years [2][3][4][5][6][7][8]. Here, we focus on the structure-function of TRAIL and extend our discussion to other members of the TNFSF/TNFRSF to illustrate the mechanism of signaling by reviewing the most up-to-date and relevant information from the scientific literature.…”

Section: Introductionmentioning

confidence: 99%

On the TRAIL of Better Therapies: Understanding TNFRSF Structure-Function

Vanamee

Faustman

2020

Cells

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Tumor necrosis factor (TNF) superfamily ligands show diverse biological functions, such as the induction of apoptotic cell death or cell survival and proliferation, making them excellent therapeutic targets for cancer and autoimmunity. We review the latest literature on TNF receptor superfamily signaling with a focus on structure-function. Using combinatorics, we argue that receptors that cluster on the cell surface and are activated by membrane-bound ligands need to arrange in a highly ordered manner, as the probability of random ligand and receptor arrangements matching up for receptor activation is very low. A growing body of evidence indicates that antiparallel receptor dimers that sequester the ligand binding site cluster on the cell surface, forming a hexagonal lattice. Upon ligand binding, this arrangement puts the activated receptors at the right distance to accommodate the downstream signaling partners. The data also suggest that the same geometry is utilized regardless of receptor type. The unified model provides important clues about TNF receptor signaling and should aid the design of better therapies for cancer and various immune mediated diseases.

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“…Of the secreted protein, TRAIL was found to be highest among ascorbate-mediated proteins. TRAIL is secreted by monocytes and is classically known as an anti-tumour protein as it selectively promotes apoptosis following binding to, and ligation of, Death Receptors and Decoy Receptors on the surface of several tumour cell lines [ 58 , 59 ]. However, TRAIL signaling is more complex than originally thought, being involved in regulating immune and inflammatory cells as well [ 60 ], and promoting a tumour-supportive immune microenvironment [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Gene and Protein Expression Is Altered by Ascorbate Availability in Murine Macrophages Cultured under Tumour-Like Conditions

et al. 2021

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Tumour-associated macrophages (TAMs) are ubiquitously present in tumours and commonly associated with poor prognosis. In immune cells, ascorbate affects epigenetic regulation, differentiation and phenotype via its co-factor activity for the 2-oxoglutarate dependent dioxygenase enzymes. Here, we determined the effect of ascorbate on TAM development in response to tumour microenvironmental cues. Naïve murine bone marrow monocytes were cultured with Lewis Lung Carcinoma conditioned media (LLCM) or macrophage colony-stimulating factor (MCSF) to encourage the development into tumour-associated macrophages. Cells were stimulated with hypoxia (1% O2), with or without ascorbate (500 µM) supplementation. Cells and media were harvested for gene, cell surface marker and protein analyses. LLCM supported bone marrow monocyte growth with >90% of cells staining CD11b+F4/80+, indicative of monocytes/macrophages. LLCM-grown cells showed increased expression of M2-like and TAM genes compared to MCSF-grown cells, which further increased with hypoxia. In LLCM-grown cells, ascorbate supplementation was associated with increased F4/80 cell surface expression, and altered gene expression and protein secretion. Our study shows that ascorbate modifies monocyte phenotype when grown under tumour microenvironmental conditions, but this was not clearly associated with either a pro- or anti-tumour phenotype, and reflects a complex and nuanced response of macrophages to ascorbate. Overall, ascorbate supplementation clearly has molecular consequences for TAMs, but functional and clinical consequences remain unknown.

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The Role of TRAIL/DRs in the Modulation of Immune Cells and Responses

Cited by 45 publications

References 331 publications

The immune system on the TRAIL of Alzheimer’s disease

The immune system on the TRAIL of Alzheimer’s disease

On the TRAIL of Better Therapies: Understanding TNFRSF Structure-Function

Gene and Protein Expression Is Altered by Ascorbate Availability in Murine Macrophages Cultured under Tumour-Like Conditions

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