Targeting sTNF/TNFR1 Signaling as a New Therapeutic Strategy

Fischer, Roman; Kontermann, Roland E.; Maier, Olaf

doi:10.3390/antib4010048

Cited by 71 publications

(73 citation statements)

References 122 publications

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“…TNFR1 is a major receptor for TNFα, mediates apoptosis, and functions as a regulator of inflammation [21]. Our cellular uptake assay results indicated that TNFα increases the cellular uptake of AgNPs.…”

Section: Resultsmentioning

confidence: 79%

Silver nanoparticles reduce the apoptosis induced by tumor necrosis factor-α

Fehaid

Taniguchi

2018

Science and Technology of Advanced Materials

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Silver nanoparticles (AgNPs) are widely known to have anti-inflammatory properties, but the exact mechanism underlying this anti-inflammatory effect is not clearly understood. Tumor necrosis factor-α (TNFα) is a major pro-inflammatory cytokine that is expressed in the early stage of cell inflammation and induces apoptosis by several known pathways. Our study aimed to investigate the effect of AgNPs on the response of lung epithelial cells to TNFα and the molecular mechanism of this response. Lung epithelial cell line NCI-H292 cells were exposed to AgNPs (5 µg/mL) and/or TNFα (20 ng/mL) for 24 h, then cellular uptake was analyzed using flow cytometry. Our results showed that AgNPs were taken up by cells in a dose-dependent manner and that the cellular uptake ratio of AgNPs was significantly increased in the presence of TNFα. Apoptosis assays indicated that exposure to AgNPs significantly decreased the apoptotic effect of TNFα. Confocal microscopy was used to localize the tumor necrosis factor receptor 1 (TNFR1) and revealed that TNFR1 localized on the surface of cells exposed to TNFα. In contrast, TNFR1 localized inside cells exposed to both AgNPs and TNFα, with very few receptors scattered on the cell membrane. The results indicated that AgNPs reduced the cell surface TNFR1 expression level. The results suggested that the reduction of surface TNFR1 reduced cellular response to TNFα, resulting in an anti-apoptotic effect.

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Section: Resultsmentioning

confidence: 79%

Silver nanoparticles reduce the apoptosis induced by tumor necrosis factor-α

Fehaid

Taniguchi

2018

Science and Technology of Advanced Materials

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“…Further, for neuronal cells, it was shown previously that proper TNFR2 activation induces protection from excitotoxicity in vitro (15,16); in the in vivo model analyzed here, in neurons in the vicinity of the acute insult and not immediately succumbing to excitotoxic death, competition of TNFRs for limiting amounts of endogenously produced membrane form of TNF exists, which results in suboptimal activation of TNFR2 of this cell population under a nontreatment condition. Moreover, at the level of intracellular signaling, it is known that signal cross-talk between TNFR1 and 2 exists in terms of competition for common signal transducers such as TRAF2 (33)(34)(35), with TNFR1 outperforming TNFR2 pathways in the case of abundance of soluble TNF, which triggers exclusively TNFR1 (3,6). In the presence of ATROSAB, neuronal response is shifted toward neuroprotective TNFR2 signaling because of blocked neuronal TNFR1, allowing the induction of a resistant state by endogenous tmTNF (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Next to induction or aggravation of demyelinating diseases, all anti-TNF therapeutics may induce severe side effects such as serious infections, including reactivation of tuberculosis and invasive fungal and other opportunistic infections. An increased susceptibility to develop additional autoimmune diseases and lymphomas has also been reported (3).…”

mentioning

confidence: 99%

“…Elevated TNF levels have been associated with different autoimmune diseases, and deregulation of TNF expression and signaling can lead to chronic inflammation and tissue damage (3)(4)(5)(6). Therefore, several anti-TNF therapeutics are clinically approved and successfully used to treat autoimmune diseases, such as rheumatoid arthritis, psoriasis, or inflammatory bowel disease.…”

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confidence: 99%

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Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

Dong

Fischer

Naudé

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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135

158

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Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNF R2 , an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNF R2 into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases.

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“…The major difference between the two receptors has been reported to be the presence of a death domain in TNFR1 and absence of a death domain in TNFR2 [4]. TNF has been found to activate proapoptotic signaling cascade through TNFR1 [5] which is expressed in various types of cells, tissues [6] and tumors [7]. Studies have shown that antibodies against TNFR1 mimic the effect of TNF-α [8,9] and as a result initiate the apoptosis process.…”

Section: Introductionmentioning

confidence: 99%