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March 25, 2002
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The Journal of Neuroscience, 2002, 22:RC216:1-7
RAPID COMMUNICATION
Neurodegenerative and Neuroprotective Effects of Tumor Necrosis
Factor (TNF) in Retinal Ischemia: Opposite Roles of TNF Receptor 1 and
TNF Receptor 2
Valerie
Fontaine1,
Saddek
Mohand-Said2,
Noelle
Hanoteau2,
Céline
Fuchs2,
Klaus
Pfizenmaier1, and
Ulrich
Eisel1
1 Institute of Cell Biology and Immunology, University
of Stuttgart, 70569 Stuttgart, Germany, and 2 Laboratoire
de Physiopathologie Cellulaire et Moléculaire de la Rétine,
Institut National de la Santé et de la Recherche Médicale
EMI 99-18, BP 426, 67091 Strasbourg, France
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.
Key words:
Akt/PKB activation; neuronal TNF and TNF-R expression; retinal cell layers; ischemia; neuroprotection; knock-out mouse; immunohistology
Copyright © Society for Neuroscience 0270-6474//$05.00/0
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