VEGF and vascular changes in chronic neuroinflammation

Kirk, S.L; Karlik, Stephen J.

doi:10.1016/s0896-8411(03)00139-2

Cited by 89 publications

(70 citation statements)

References 33 publications

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“…22 Because TWEAK promotes angiogenesis 21 and TRAIL inhibits it, 76 there is the intriguing possibility that Fn14-TRAIL may inhibit angiogenesis at inflammatory sites by a dual mechanism, that is, by antagonizing TWEAK's proangiogenic activity and synergistically reinforcing this effect through TRAIL's anti-angiogenic activity.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, TWEAK has pro-angiogenic activity, 21 which is of interest given the association between angiogenesis and autoimmune pathogenesis. 22 TWEAK increases EAE severity and associated neurodegeneration, 14,23,24 and circulating TWEAK levels are significantly increased in patients with MS and other chronic inflammatory diseases. 6 The induction of inhibitory anti-TWEAK or Fn14 antibody (Ab) in vivo, via vaccination with the extracellular domains of either TWEAK or Fn14, ameliorates EAE manifestations in rat and mouse models.…”

mentioning

confidence: 99%

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Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Razmara

Hilliard

Ziarani

et al. 2009

The American Journal of Pathology

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Hallmarks of the pathogenesis of autoimmune encephalomyelitis include perivascular infiltration of inflammatory cells into the central nervous system, multifocal demyelination in the brain and spinal cord, and focal neuronal degeneration. Optimal treatment of this complex disease will ultimately call for agents that target the spectrum of underlying pathogenic processes. In the present study, Fn14-TRAIL is introduced as a unique immunotherapeutic fusion protein that is designed to exchange and redirect intercellular signals within inflammatory cell networks, and, in so doing, to impact multiple pathogenic events and yield a net anti-inflammatory effect. In this soluble protein product, a Fn14 receptor component (capable of blocking the pro-inflammatory TWEAK ligand) is fused to a TRAIL ligand (capable of inhibiting activated, pathogenic T cells). Sustained Fn14-TRAIL expression was obtained in vivo using a transposon-based eukaryotic expression vector. Fn14-TRAIL expression effectively prevented chronic, nonremitting, paralytic disease in myelin oligodendrocyte glycoprotein-challenged C57BL/6 mice. Disease suppression in this model was reflected by decreases in the clinical score, disease incidence, nervous tissue inflammation, and Th1, Th2, and Th17 cytokine responses. Significantly, the therapeutic efficacy of Fn14-TRAIL could not be recapitulated simply by administering its component parts (Fn14 and TRAIL) as soluble agents, either alone or in combination. Its functional pleiotropism was manifest in its additional ability to attenuate the enhanced permeability of the blood-brain barrier that typically accompanies autoimmune encephalomyelitis. (Am J Pathol

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Razmara

Hilliard

Ziarani

et al. 2009

The American Journal of Pathology

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show abstract

“…7B), spinal cords from CXCR3 Ϫ/Ϫ mice with EAE showed significantly worse BBB disruption, as compared with CXCR3 ϩ/ϩ animals. Inflammation that occurs during EAE can lead to angiogenesis, associated with reduced BBB integrity (65,66). We assessed vascular density at the peak of EAE in CXCR3 ϩ/ϩ and CXCR3…”

Section: Increased Permeability Of Bbb In Cxcr3mentioning

confidence: 99%

Severe Disease, Unaltered Leukocyte Migration, and Reduced IFN-γ Production in CXCR3−/− Mice with Experimental Autoimmune Encephalomyelitis

Liu

Huang

Matsui

et al. 2006

The Journal of Immunology

135

112

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Experimental autoimmune encephalomyelitis (EAE) is a CD4+ Th1 T cell-mediated disease of the CNS, used to study certain aspects of multiple sclerosis. CXCR3, the receptor for CXCL10, CXCL9, and CXCL11, is preferentially expressed on activated Th1 T cells and has been proposed to govern the migration of lymphocytes into the inflamed CNS during multiple sclerosis and EAE. Unexpectedly, CXCL10-deficient mice were susceptible to EAE, leaving uncertain what the role of CXCR3 and its ligands might play in this disease model. In this study, we report that CXCR3−/− mice exhibit exaggerated severity of EAE compared with wild-type (CXCR3+/+) littermate mice. Surprisingly, there were neither quantitative nor qualitative differences in CNS-infiltrating leukocytes between CXCR3+/+ and CXCR3−/− mice with EAE. Despite these equivalent inflammatory infiltrates, CNS tissues from CXCR3−/− mice with EAE showed worsened blood-brain barrier disruption and more von Willebrand factor-immunoreactive vessels within inflamed spinal cords, as compared with CXCR3+/+ mice. Spinal cords of CXCR3−/− mice with EAE demonstrated decreased levels of IFN-γ, associated with reduced inducible NO synthase immunoreactivity, and lymph node T cells from CXCR3−/− mice primed with MOG35–55 secreted less IFN-γ in Ag-driven recall responses than cells from CXCR3+/+ animals. CXCR3−/− lymph node T cells also showed enhanced Ag-driven proliferation, which was reduced by addition of IFN-γ. Taken with prior findings, our data show that CXCL10 is the most relevant ligand for CXCR3 in EAE. CXCR3 does not govern leukocyte trafficking in EAE but modulates T cell IFN-γ production and downstream events that affect disease severity.

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“…The VEGFR antagonist, Cyclo-VEGI, reduces inflammation and vascular leakiness, and is neuroprotective against excitotoxin-induced neurodegeneration in rats (Ryu and McLarnon 2008). This suggests dysregulated VEGF expression in the PD brain is also a key part of the neuroinflammatory response and increased edema in PD (Kirk and Karlik 2003;Suidan, Dickerson et al 2010) (Nguyen, Julien et al 2002;Nguyen, Tatlipinar et al 2006;Zhang, Wang et al 2006). It is also worth noting that the innate immune cells of the brain, including microglia, become more reactive with age and that this might contribute to increased neuroinflammation in the elderly at some time point after activation of the peripheral immune response (Godbout and Johnson 2009).…”

Section: Inflammatory Responses and Regulation In Parkinson's Diseasementioning

confidence: 99%

Inflammatory Responses and Regulation in Parkinson’s Disease

Peterson¹,

Flood²

2011

Etiology and Pathophysiology of Parkinson's Disease

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VEGF and vascular changes in chronic neuroinflammation

Cited by 89 publications

References 33 publications

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Severe Disease, Unaltered Leukocyte Migration, and Reduced IFN-γ Production in CXCR3−/− Mice with Experimental Autoimmune Encephalomyelitis

Inflammatory Responses and Regulation in Parkinson’s Disease

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