Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Fischer, Roman; Kontermann, Roland E.; Pfizenmaier, Klaus

doi:10.3389/fcell.2020.00401

Cited by 152 publications

(153 citation statements)

References 213 publications

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“…Indeed, the use of selective conditional KO mice has highlighted subtle but relevant differences in the function of TNFR1 and TNFR2 in a cell- and context-dependent manner [ 116 , 126 ]. Moreover, as perceptively reviewed elsewhere [ 130 , 201 ], new molecules designed to target TNF signaling have been developed and are under investigation in several disease models, including neurodegenerative diseases. It is worth noting that the selective solTNF inhibitor XPro1595, one of the best studied compounds in experimental MS, has recently entered a phase-1 clinical trial in mild to moderate AD patients (ClinicalTrials.gov identifier-NCT number: NCT03943264).…”

Section: Discussionmentioning

confidence: 99%

“…The individual roles of the two TNF-TNFR signaling pathways have also been investigated by pharmacological treatments in the EAE model, providing solid and convincing evidence that the specific inhibition of solTNF or TNFR1 is beneficial in EAE and may represent a valuable anti-TNF therapy for MS. The selective inhibition of solTNF through Xpro1595, which does not alter tmTNF signaling, has been studied by different groups and has proven a promising therapeutic strategy [ 130 ]. Treatment of EAE mice with Xpro1595 resulted protective in disease progression, while blocking both soluble and transmembrane TNF through etanercept failed to reduce clinical symptoms [ 119 , 120 ].…”

Section: Evidence For Tnf Involvement In Pathological Hallmarks Ofmentioning

confidence: 99%

“…Based on the recognized role of TNF in autoimmune disorders, since 1988 different drugs targeting TNF signaling have been successfully introduced for the treatment of inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease and ankylosing spondylitis, psoriasis [ 186 , 187 , 188 ]. Over time, the pharmacological armamentarium has improved moving from the first pan-anti-TNF drugs, which resulted in a nonselective inhibition of TNF signaling, to the more recent TNFR1- and TNFR2-targeted macro- or nanomolecules [ 130 ].…”

Section: Targeting Tnf Signaling As a Therapy For Msmentioning

confidence: 99%

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Re-Examining the Role of TNF in MS Pathogenesis and Therapy

Fresegna

Bullitta

Musella

et al. 2020

Cells

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Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical and experimental studies delineate abnormal expression of specific cytokines over the course of the disease. One major cytokine that has been shown to play a pivotal role in MS is tumor necrosis factor (TNF). TNF is a pleiotropic cytokine regulating many physiological and pathological functions of both the immune system and the central nervous system (CNS). Convincing evidence from studies in human and experimental MS have demonstrated the involvement of TNF in various pathological hallmarks of MS, including immune dysregulation, demyelination, synaptopathy and neuroinflammation. However, due to the complexity of TNF signaling, which includes two-ligands (soluble and transmembrane TNF) and two receptors, namely TNF receptor type-1 (TNFR1) and type-2 (TNFR2), and due to its cell- and context-differential expression, targeting the TNF system in MS is an ongoing challenge. This review summarizes the evidence on the pathophysiological role of TNF in MS and in different MS animal models, with a special focus on pharmacological treatment aimed at controlling the dysregulated TNF signaling in this neurological disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Evidence For Tnf Involvement In Pathological Hallmarks Ofmentioning

confidence: 99%

Section: Targeting Tnf Signaling As a Therapy For Msmentioning

confidence: 99%

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Re-Examining the Role of TNF in MS Pathogenesis and Therapy

Fresegna

Bullitta

Musella

et al. 2020

Cells

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“…Therefore, it is conceivable that YB-1/PGRN interferes with oligomer formation and thereby prevents signal transduction. Determining the structure of these interactions is essential, as this may reveal new targets for development as anti-TNF therapy, as current therapies although successful have their limitations [ 78 ]. How YB-1/PGRN influence membrane-bound ligand activity requires further study.…”

Section: Discussionmentioning

confidence: 99%

YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling

Hessman

Hildebrandt

Shah

et al. 2020

IJMS

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Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor α (TNFα) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNFα-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNFα to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNFα-mediated signaling, supporting the functionality with an NF-κB luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNFα to its receptors and influencing TNFα-mediated signaling via its interaction with progranulin.

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“…The anti-inflammatory effects of signaling through TNFRII were also demonstrated by administration of the TNFRII-specific agonist TNCscTNF80 to a mouse CIA model [ 45 ]. To reduce adverse events due to global inhibition of TNF-mediated effects, therapeutics based on specifically targeting TNFRI with antagonists or targeting TNFRII with agonists are currently in preclinical and early clinical stages of development [ 46 ].…”

Section: Jnk Participates In Signaling By Critical Proinflammatorymentioning

confidence: 99%

Activation of c-Jun N-Terminal Kinase, a Potential Therapeutic Target in Autoimmune Arthritis

Lai

2020

Cells

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The c-Jun-N-terminal kinase (JNK) is a critical mediator involved in various physiological processes, such as immune responses, and the pathogenesis of various diseases, including autoimmune disorders. JNK is one of the crucial downstream signaling molecules of various immune triggers, mainly proinflammatory cytokines, in autoimmune arthritic conditions, mainly including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. The activation of JNK is regulated in a complex manner by upstream kinases and phosphatases. Noticeably, different subtypes of JNKs behave differentially in immune responses. Furthermore, aside from biologics targeting proinflammatory cytokines, small-molecule inhibitors targeting signaling molecules such as Janus kinases can act as very powerful therapeutics in autoimmune arthritis patients unresponsiveness to conventional synthetic antirheumatic drugs. Nevertheless, despite these encouraging therapies, a population of patients with an inadequate therapeutic response to all currently available medications still remains. These findings identify the critical signaling molecule JNK as an attractive target for investigation of the immunopathogenesis of autoimmune disorders and for consideration as a potential therapeutic target for patients with autoimmune arthritis to achieve better disease control. This review provides a useful overview of the roles of JNK, how JNK is regulated in immunopathogenic responses, and the potential of therapeutically targeting JNK in patients with autoimmune arthritis.

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Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Cited by 152 publications

References 213 publications

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling

Activation of c-Jun N-Terminal Kinase, a Potential Therapeutic Target in Autoimmune Arthritis

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