TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury

Abstract

CNS neurons use robust cytoprotective mechanisms to ensure survival and functioning under conditions of injury. These involve pathways induced by endogenous neuroprotective cytokines such as erythropoietin (EPO). Recently, in contrast to its well known deleterious roles, TNF has also been shown to exhibit neuroprotective properties. In the present study, we investigated the molecular mechanisms by which TNF receptor (TNFR)I mediates neuroprotection by comparing the gene expression profiles of lesioned cortex from WT and TNFRI KO mice after permanent middle cerebral artery occlusion. Several known neuroprotective molecules were identified as TNFRI targets, notably members of the Bcl-2 family, DNA repair machinery and cell cycle, developmental, and differentiation factors, neurotransmitters and growth factors, as well as their receptors, including EPO receptor (EPOR), VEGF, colony-stimulating factor receptor 1, insulin-like growth factor (IGF), and nerve growth factor (NGF). Further analysis showed that induction of EPOR and VEGF expression in primary cortical neurons after glucose deprivation (GD) largely depended on TNFRI and was further up-regulated by TNF. Also, EPO-and VEGFinduced neuroprotection against GD, oxygen-glucose deprivation, and NMDA excitotoxicity depended significantly on TNFRI presence. Finally, EPO prevented neuronal damage induced by kainic acid in WT but not TNFRI KO mice. Our results identify cross-talk between tissue protective cytokines, specifically that TNFRI is necessary for constitutive and GD-induced expression of EPOR and VEGF and for EPOmediated neuroprotection.cDNA microarray ͉ cytokine signaling ͉ neuron death ͉ transgenic mice ͉ epilepsy

Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns

“…Other evidence of an effect on TNF-α signaling comes from studies with recombinant EPO. For example, EPO inhibited TNF-α-induced apoptosis of SH-SY5Y cells in vitro (28) as well as counteracted and reversed TNF-α-mediated effects in different in vivo models of neuronal injury (29,30). On the other hand, EPO has also been shown to induce TNF-α and apoptosis in a liver regeneration model (31).…”

Tumor Necrosis Factor-α (TNF-α) Regulates Shedding of TNF-α Receptor 1 by the Metalloprotease-Disintegrin ADAM8: Evidence for a Protease-Regulated Feedback Loop in Neuroprotection

“…In particular, TNF-R1 signaling is instrumental in mediating neuroprotective effects (Taoufik et al, 2008), i.e., by inducing intracellular neuroprotective pathways (MAP, phosphatidylinositol 3-kinase) or by scavenging extracellular TNF-␣ through binding to sTNF-R1. The importance of systemic TNF-R1 shedding has been demonstrated in TRAPS (TNF receptor associated periodic syndrome) (McDermott et al, 1999;Hull et al, 2002) patients with mutations in TNF-R1 leading to shedding deficiency (Galon et al, 2000) and in TRAPS model mice expressing a knock-in non-sheddable TNF-R1 (TNF-R1⌬ NS ) variant (Xanthoulea et al, 2004).…”

The Receptor That Tames the Innate Immune Response

“…An initial phase of the innate immune response (which consists of proinflammatory cytokine production) strongly upregulates the TPR (Figure 1, stages 2-3). For example, tumor necrosis factor receptor 1 (TNFR1) is required for upregulation of EPOR as well as enabling the therapeutic effects of EPO in the mouse (75). Therefore, TNFR1 KO mice exhibit greater injury after brain ischemia (76), and as predicted, do not respond to EPO when exposed to a neurotoxin (75).…”