A Soluble Fn14-Fc Decoy Receptor Reduces Infarct Volume in a Murine Model of Cerebral Ischemia

Yepes, Manuel; Brown, Sharron A.N.; Moore, Elizabeth; Smith, E. L.; Lawrence, Daniel A.; Winkles, Jeffrey A.

doi:10.1016/s0002-9440(10)62273-0

Cited by 115 publications

(159 citation statements)

References 43 publications

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Section: Tweak Gene Expressionmentioning

confidence: 99%

“…Indeed, TWEAK mRNA and/or protein expression has been detected in many different tissues 4,5,19,[22][23][24][25] and tumour specimens 20,23,26,27 . TWEAK is also expressed in primary murine neurons 28 and astrocytes 28,29 , in monocytes/ macrophages 4,21,22,30,31 and in various human tumour cell lines 4,5,20,26, 27. It has been reported that IFN-γ30 , 32 or phorbol myristate acetate 30 treatment of human primary monocytes can increase TWEAK levels, as determined by fluorescence-activated cell-sorter analysis.…”

Section: Tweak Gene Expressionmentioning

confidence: 99%

See 1 more Smart Citation

The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

Winkles

2008

Nat Rev Drug Discov

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525

662

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TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. TWEAK acts by binding to Fn14, a highly inducible cell-surface receptor that is linked to several intracellular signalling pathways, including the nuclear factor-κB (NF-κB) pathway. The TWEAK-Fn14 axis normally regulates various physiological processes, in particular it seems to play an important, beneficial role in tissue repair following acute injury. Furthermore, recent studies have indicated that TWEAK-Fn14 axis signalling may contribute to cancer, chronic autoimmune diseases and acute ischaemic stroke. This Review provides an overview of TWEAK-Fn14 axis biology and summarizes the available data supporting the proposal that both TWEAK and Fn14 should be considered as potential targets for the development of novel therapeutics.Cytokines are a large and diverse group of plasma-membrane-associated or secreted proteins that bind cell-surface receptors and thereby regulate many important biological processes. These processes include development, haematopoesis, inflammation, immune responses and tissue repair1. The tumour necrosis factor (TNF) ligand superfamily, and the receptors that mediate their effects, is a cytokine-receptor subgroup that has attracted considerable interest as a potential source of therapeutic targets for the management of complex human diseases. TNF superfamily ligands are primarily expressed as type II transmembrane proteins, but in some cases they are processed into smaller, secreted proteins that retain biological activity2 , 3. Both the anchored and soluble cytokines contain a C-terminal TNF homology domain that mediates self-trimerization and receptor binding. TNF superfamily members bind to one or more members of the TNF receptor (TNFR) superfamily, most of which are type I or type III transmembrane proteins2 , 3. These receptors are characterized by the presence of an extracellular, ligand-binding region containing one to four cysteine-rich domains and a cytoplasmic tail containing one or more adaptor-protein binding sites. TWEAK (also known as TNFSF12, APO3L, CD255) and its cognate receptor Fn14 (also known as TNFRSF12A, TWEAKR, CD266) are members of the TNF and TNFR superfamilies, respectively, and the discovery of this cytokine-receptor axis was in itself an interesting scientific journey. In 1997, Chicheportiche et al. 4 reported the identification of a novel TNF-like protein that had pro-apoptotic activity on interferon-α (IFN-γ)-treated human HT-29 colon carcinoma cells. Consequently, they named this cytokine TNF-like weak inducer of apoptosis (abbreviated to TWEAK). These investigators were recipients of unexpected good fortune, as they were not originally aiming to identify new TNF superfamily members; indeed, the TWEAK cDNA was cloned during a screen for erythropoietin-related mRNAs in mouse macrophages. In 1998, Marsters et al. 5 reported the identification of the same protein by searching an expre...

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Section: Tweak Gene Expressionmentioning

confidence: 99%

Section: Tweak Gene Expressionmentioning

confidence: 99%

The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

Winkles

2008

Nat Rev Drug Discov

Self Cite

525

662

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“…TNFa, TNFb, FasL, TRAIL, and TWEAK). [85][86][87][88][89][90] The interaction of these ligands with their receptors, including TNF receptor 1, FasR, death receptor 4, death receptor 5, and TWEAKR, expressed by oligodendrocyte progenitor cells and neurons, can trigger apoptotic cell death. Death receptor activation triggers an extrinsic pathway of caspase-dependent cell death, or produces truncated Bid, leading to enhancement of Bax-dependent mitochondrial pore formation and cell death.…”

Section: Death Receptorsmentioning

confidence: 99%

“…TRAIL and TWEAK have been shown to be important mediators of cell death in adult models of injury. 88,97 Recently, we have published evidence implicating these proteins as mediators of neonatal hypoxia-ischaemia, 98 and another study has implicated them as regulators of cell cycle arrest and neurite outgrowth. The latter functions can be attributed to the anti-apoptotic effects exerted by TNF receptor 2 99 and TWEAKR.…”

Section: Death Receptorsmentioning

confidence: 99%

Inflammation‐induced sensitization of the brain in term infants

Fleiss

Tann

Degos

et al. 2015

Develop Med Child Neuro

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COXPerinatal insults are a leading cause of infant mortality and amongst survivors are frequently associated with neurocognitive impairment, cerebral palsy (CP), and seizure disorders. The events leading to perinatal brain injury are multifactorial. This review describes how one subinjurious factor affecting the brain sensitizes it to a second injurious factor, causing an exacerbated injurious cascade. We will review the clinical and experimental evidence, including observations of high rates of maternal and fetal infections in term-born infants with neonatal encephalopathy and cerebral palsy. In addition, we will discuss preclinical evidence for the sensitizing effects of inflammation on injuries, such as hypoxia-ischaemia, our current understanding of the mechanisms underpinning the sensitization process, and the possibility for neuroprotection. PERINATAL BRAIN INJURY IN THE TERM-BORN INFANTIntrapartum neonatal deaths are the third leading cause of global childhood mortality. 1 In addition, each year perinatal insults are estimated to be responsible for more than one million new cases of neonatal encephalopathy, and nearly half a million infants with impairments such as cerebral palsy (CP).2 Infants exposed to a perinatal insult typically present with encephalopathy, a descriptive term for a clinical constellation of neurological dysfunctions in the term-born that includes difficulty with initiating and maintaining respiration; depression of tone and reflexes; subnormal levels of consciousness; and seizures.3 Whilst often assumed to result solely from acute intrapartum hypoxic-ischaemia, the precise contribution of hypoxia is likely to vary according to the definition of encephalopathy used, the range of competing risks, and the care setting. 3,4 Presumed hypoxia-ischaemia is diagnosed based on reduced Apgar scores and acidosis, 5 and the combination of progressive hypoxia, hypercarbia, and acidosis is often referred to as asphyxia. 6 Encephalopathy resulting from hypoxia-ischaemia can be clearly diagnosed only in a small number of cases in which a sentinel event, such as placental abruption, uterine rupture, cord prolapse, or shoulder dystocia, is clearly present. Clinical studies have identified a number of other important antepartum and intrapartum risk factors for neonatal encephalopathy. [7][8][9][10] In low-income settings, where access to skilled birth attendants and emergency obstetric intervention is often limited, the probability of intrapartum hypoxic events contributing to neonatal encephalopathy is increased.2,9,11 However, in general, neonatal encephalopathy is likely to be a multifactorial condition with complex aetiology, encompassing several causal events, with strong evidence that fetal exposure to infection contributes. 12 CONCEPT OF INFLAMMATION-INDUCED SENSITIZATIONAn increasingly common model for the complex and multifactorial process of perinatal brain injury involves sensitization, 13-15 whereby factors not severe enough by themselves to induce significant brain damage make the developi...

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“…These studies showed that TWEAK and Fn14 expression increases in the area of ischemic penumbra after middle cerebral artery occlusion (MCAO) in the mouse (Potrovita et al, 2004;Yepes et al, 2005) and that inhibition of TWEAK activity either with a soluble Fn14-Fc decoy receptor (Polavarapu et al, 2005) or with neutralizing anti-TWEAK antibodies (Potrovita et al, 2004) is neuroprotective.…”

Section: Introductionmentioning

confidence: 99%

TWEAK—Fn14 Pathway Inhibition Protects the Integrity of the Neurovascular Unit during Cerebral Ischemia

Zhang

Winkles

Góngora

et al. 2006

J Cereb Blood Flow Metab

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104

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Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts via binding to a cell surface receptor named Fn14. To study the role of this cytokine in the regulation of the permeability of the neurovascular unit (NVU) during cerebral ischemia, TWEAK activity was inhibited in wild-type mice with a soluble Fn14-Fc decoy receptor administered either immediately or 1 h after middle cerebral artery occlusion (MCAO). Administration of Fn14-Fc decoy resulted in faster recovery of motor function and a 66.4%610% decrease in Evans blue dye extravasation when treatment was administered immediately after MCAO and a 46.1%613.1% decrease when animals were treated 1 h later (n = 4, P < 0.05). Genetic deficiency of Fn14 resulted in a 60%612.8% decrease in the volume of the ischemic lesion (n = 6, P < 0.05), and a 87%622% inhibition in Evans blue dye extravasation 48 h after the onset of the ischemic insult (n = 6, P < 0.005). Compared with control animals, treatment with Fn14-Fc decoy or genetic deficiency of Fn14 also resulted in a significant inhibition of nuclear factor-jB pathway activation, matrix metalloproteinase-9 activation and basement membrane laminin degradation after MCAO. These findings show that the cytokine TWEAK plays a role in the disruption of the structure of the NVU during cerebral ischemia and that TWEAK antagonism is a potential therapeutic strategy for acute cerebral ischemia.

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A Soluble Fn14-Fc Decoy Receptor Reduces Infarct Volume in a Murine Model of Cerebral Ischemia

Cited by 115 publications

References 43 publications

The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

Inflammation‐induced sensitization of the brain in term infants

TWEAK—Fn14 Pathway Inhibition Protects the Integrity of the Neurovascular Unit during Cerebral Ischemia

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