Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2.
Tumor necrosis factor (TNF) is an important factor in various acute and chronic neurodegenerative disorders. In retinal ischemia, we show early, transient upregulation of TNF, TNF receptor 1 (TNF-R1), and TNF-R2 6 hr after reperfusion preceding neuronal cell loss. To assess the specific role of TNF and its receptors, we compared ischemia-reperfusion-induced retinal damage in mice deficient for TNF-R1, TNF-R2, or TNF by quantifying neuronal cell loss 8 d after the insult. Surprisingly, TNF deficiency did not affect overall cell loss, yet absence of TNF-R1 led to a strong reduction of neurodegeneration and lack of TNF-R2 led to an enhancement of neurodegeneration, indicative of TNF-independent and TNF-dependent processes in the retina, with TNF-R1 augmenting neuronal death and TNF-R2 promoting neuroprotection. Western blot analyses of retinas revealed that reduction of neuronal cell loss in TNF-R1/ animals correlated with the presence of activated Akt/protein kinase B (PKB). Inhibition of the phosphatidylinositol 3-kinase signaling pathway reverted neuroprotection in TNF-R1-deficient mice, indicating an instrumental role of Akt/PKB in neuroprotection and TNF-R2 dependence of this pathway. Selective inhibition of TNF-R1 function may represent a new approach to reduce ischemia-induced neuronal damage, being potentially superior to strategies aimed at suppression of TNF activity in general.
Fontaine
Valerie
V
Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany.
Mohand-Said
Saddek
S
Hanoteau
Noelle
N
Fuchs
Céline
C
Pfizenmaier
Klaus
K
Eisel
Ulrich
U
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D012160:Retina / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D012164:Retinal Diseases / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D012171:Retinal Vessels / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation
D015703:Antigens, CD; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha