Reverse Signaling of Tumor Necrosis Factor Superfamily Proteins in Macrophages and Microglia: Superfamily Portrait in the Neuroimmune Interface

Lee, Won‐Ha; Seo, Donggun; Lim, Su-Geun; Suk, Kyoungho

doi:10.3389/fimmu.2019.00262

Cited by 26 publications

(21 citation statements)

References 260 publications

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“…The production of EVs containing TNFR1 and associated TRADD proteins was described to be triggered by TNF itself as a feedback mechanism, capable to inhibit TNF-induced responses in parental cells and to prevent excessive inflammatory activity [ 81 ]. Furthermore, the release of TNF receptors through EVs may represent a mechanism of intercellular communication, as vesicular TNFR1 binding to tmTNF on the surface of target cells, acting in this case as a receptor, might activate a “reverse” signaling mechanism [ 83 , 84 ]. Indeed, tmTNF presents an intracellular domain containing a nuclear localization sequence of 10 kDa, which is able to detach upon tmTNF binding with soluble receptors [ 84 ] and to induce a specific anti-inflammatory response in tmTNF-bearing cells [ 85 ].…”

Section: Tnf Release Via Extracellular Vesicles (Evs)mentioning

confidence: 99%

“…Furthermore, the release of TNF receptors through EVs may represent a mechanism of intercellular communication, as vesicular TNFR1 binding to tmTNF on the surface of target cells, acting in this case as a receptor, might activate a “reverse” signaling mechanism [ 83 , 84 ]. Indeed, tmTNF presents an intracellular domain containing a nuclear localization sequence of 10 kDa, which is able to detach upon tmTNF binding with soluble receptors [ 84 ] and to induce a specific anti-inflammatory response in tmTNF-bearing cells [ 85 ]. Interestingly, the same process can be activated also by the interaction between tmTNF and TNF-targeting drugs, i.e., monoclonal antibodies, crucially contributing to the positive outcome of the pharmacological treatment [ 86 ].…”

Section: Tnf Release Via Extracellular Vesicles (Evs)mentioning

confidence: 99%

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TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

Raffaele

Lombardi

Verderio

et al. 2020

Cells

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Tumor necrosis factor (TNF) is a pleiotropic cytokine powerfully influencing diverse processes of the central nervous system (CNS) under both physiological and pathological conditions. Here, we analyze current literature describing the molecular processes involved in TNF synthesis and release from microglia, the resident immune cells of the CNS and the main source of this cytokine both in brain development and neurodegenerative diseases. A special attention has been given to the unconventional vesicular pathway of TNF, based on the emerging role of microglia-derived extracellular vesicles (EVs) in the propagation of inflammatory signals and in mediating cell-to-cell communication. Moreover, we describe the contribution of microglial TNF in regulating important CNS functions, including the neuroinflammatory response following brain injury, the neuronal circuit formation and synaptic plasticity, and the processes of myelin damage and repair. Specifically, the available data on the functions mediated by microglial EVs carrying TNF have been scrutinized to gain insights on possible novel therapeutic strategies targeting TNF to foster CNS repair.

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Section: Tnf Release Via Extracellular Vesicles (Evs)mentioning

confidence: 99%

Section: Tnf Release Via Extracellular Vesicles (Evs)mentioning

confidence: 99%

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

Raffaele

Lombardi

Verderio

et al. 2020

Cells

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“…The tumor necrosis factor (TNF) superfamily (TNFSF) is a superfamily of type II transmembrane proteins commonly containing the TNF homology domain [12]. This superfamily consists of more than 20 protein members, which can be released from the cell membrane by proteolytic cleavage by specific metalloproteinases to generate soluble cytokines [13].…”

Section: The Rank/rankl Signaling Networkmentioning

confidence: 99%

“…This superfamily consists of more than 20 protein members, which can be released from the cell membrane by proteolytic cleavage by specific metalloproteinases to generate soluble cytokines [13]. The members of the TNFSF have in common that they interact with their cognate TNF receptor superfamily (TNFRSF) members [12,14]. Conserved residues provide specific inter subunit contacts.…”

Section: The Rank/rankl Signaling Networkmentioning

confidence: 99%

“…Conserved residues provide specific inter subunit contacts. There is substantial crosstalk among related ligand receptor pairs and cytokines, and recent evidence suggests that signals can be generated from the receptor part (forward signaling) as well from the ligand part (reverse signaling) [12]. The TNFSF/TNFRSF axes are involved in regulating diverse biological processes, including embryogenesis, differentiation, proliferation, apoptosis, inflammation, and immune responses [14,15].…”

Section: The Rank/rankl Signaling Networkmentioning

confidence: 99%

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RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review

Dam

Verhoeven

Jacobs

et al. 2019

IJMS

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RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG), but also has additional more complex levels of regulation. The existing literature on RANK/RANKL signaling in cervical cancer was reviewed, particularly focusing on the effects on the microenvironment. RANKL and RANK are frequently co-expressed in cervical cancer cells lines and in carcinoma of the uterine cervix. RANKL and OPG expression strongly increases during cervical cancer progression. RANKL is directly secreted by cervical cancer cells, which may be a mechanism they use to create an immune suppressive environment. RANKL induces expression of multiple activating cytokines by dendritic cells. High RANK mRNA levels and high immunohistochemical OPG expression are significantly correlated with high clinical stage, tumor grade, presence of lymph node metastases, and poor overall survival. Inhibition of RANKL signaling has a direct effect on tumor cell proliferation and behavior, but also alters the microenvironment. Abundant circumstantial evidence suggests that RANKL inhibition may (partially) reverse an immunosuppressive status. The use of denosumab, a monoclonal antibody directed to RANKL, as an immunomodulatory strategy is an attractive concept which should be further explored in combination with immune therapy in patients with cervical cancer.

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Recombinant CD137‐Fc, its synthesis, and applications for improving the immune system functions, such as tumor immunotherapy and to reduce the inflammation due to the novel coronavirus

Ajami

Nazari

Mahmoodzadeh

et al. 2021

J of Cellular Biochemistry

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CD137 (ILA/4‐1BB), a member of tumor necrosis factor receptor superfamily, is one of the most important T cell costimulatory molecules. Interaction of this molecule with its ligand transmits a two‐way signal that activates both T lymphocyte and antigen presenting cells. The soluble form of CD137 (sCD137) reduces the activity of its membrane isoform and is associated with T lymphocyte activation‐induced cell death. Recombinant CD137‐Fc may be used to treat cancers, autoimmune disorders and viral infections. It may also be useful for management of coronavirus infection. The 1276 bp DNA sequence encoded CD137‐Fc recombinant protein was prepared and subcloned into lentiviral vector and expressed in transduced CHO‐K1 eukaryotic cells. The sodium dodecyl sulfate–polyacrylamide gel electrophoresis, Western blot analysis, and enzyme‐linked immunosorbent assay analysis results demonstrated that the expression of the 70‐kDa CD137‐Fc molecule was detectable without any degradation. This study helps to confirm previous research suggesting the use of this recombinant protein as a promising solution for the treatment of virus infections. CD137‐Fc fusion protein could also make immunotherapy more effective for some diseases. This product is widely used in novel medical treatments, including cell‐based immunotherapy such as dendritic cell, CAR T and CAR NK therapy. Its production and usage in research and treatment is noticeable also in current coronavirus disease 2019 pandemic.

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Reverse Signaling of Tumor Necrosis Factor Superfamily Proteins in Macrophages and Microglia: Superfamily Portrait in the Neuroimmune Interface

Cited by 26 publications

References 260 publications

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review

Recombinant CD137‐Fc, its synthesis, and applications for improving the immune system functions, such as tumor immunotherapy and to reduce the inflammation due to the novel coronavirus

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