Tumor necrosis factor p55 and p75 receptors are involved in chemical-induced apoptosis of dentate granule neurons

• Published in: Journal of neurochemistry Vol. 106; no. 1; pp. 281 - 298
• Main Authors: Harry, G. Jean, Lefebvre d'Hellencourt, Christian, McPherson, Christopher A, Funk, Jason A, Aoyama, Mineyoshi, Wine, Robert N
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-07-2008; Blackwell Publishing Ltd; Blackwell; Wiley
• Subjects: Ageing, cell death; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - immunology; Apoptosis Regulatory Proteins - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biological and medical sciences; Brain damage; Cell physiology; Cell receptors; Cell structures and functions; Cytokines - drug effects; Cytokines - genetics; Cytokines - metabolism; Dentate Gyrus - immunology; Dentate Gyrus - metabolism; Dentate Gyrus - pathology; Endocytosis - drug effects; Endocytosis - physiology; Fas-Associated Death Domain Protein - drug effects; Fas-Associated Death Domain Protein - genetics; Fas-Associated Death Domain Protein - metabolism; Fundamental and applied biological sciences. Psychology; hippocampus; Human health and pathology; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; microglia; Microglia - drug effects; Microglia - immunology; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); Nerve Degeneration - chemically induced; Nerve Degeneration - immunology; Nerve Degeneration - metabolism; neuroglia; neuroinflammation; Neurology; Neurons - drug effects; Neurons - immunology; Neurons - metabolism; Neurotoxins - toxicity; Receptors, Nerve Growth Factor - drug effects; Receptors, Nerve Growth Factor - genetics; Receptors, Nerve Growth Factor - metabolism; Receptors, Tumor Necrosis Factor - drug effects; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Receptors, Tumor Necrosis Factor, Type I - drug effects; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Rodents; trimethyltin; Trimethyltin Compounds - toxicity; tumor necrosis factor; Neuroglia; Central nervous system; Vitamin; Encephalon; Signal transduction; neuroinflammation; trimethyltin; Pyramidal neuron; Biological receptor; Nervous system diseases; p75 receptor; Granule neuron; hippocampus; Enzyme; Cytokine; Rodentia; Caspase; Biotin; Microglia; Cerebral disorder; Peptidases; Vertebrata; Mammalia; Mouse; Tumor necrosis factor; Cell death; Central nervous system disease; Hydrolases; Models; Apoptosis; apoptosis; tumor necrosis factor; Trimethyltin
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05382.x

Localized tumor necrosis factor-α (TNFα) elevation has diverse effects in brain injury often attributed to signaling via TNFp55 or TNFp75 receptors. Both dentate granule cells and CA pyramidal cells express TNF receptors (TNFR) at low levels in a punctate pattern. Using a model to induce selective death of dentate granule cells (trimethyltin; 2 mg/kg, i.p.), neuronal apoptosis [terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ end labeling, active caspase 3 (AC3)] was accompanied by amoeboid microglia and elevated TNFα mRNA levels. TNFp55R (55 kDa type-1 TNFR) and TNFp75R (75 kDa type-2 TNFR) immunoreactivity in AC3⁺ neurons displayed a pattern suggestive of receptor internalization and a temporal sequence of expression of TNFp55R followed by TNFp75R associated with the progression of apoptosis. A distinct ramified microglia response occurred around CA1 neurons and healthy dentate neurons that displayed an increase in the normal punctate pattern of TNFRs. Neuronal damage was decreased with i.c.v. injection of TNFα antibody and in TNFp55R-/-p75R-/- mice that showed higher constitutive mRNA levels for interleukin (IL-1α), macrophage inflammatory protein 1-α (MIP-1α), TNFα, transforming growth factor β1, Fas, and TNFRSF6-assoicated via death domain (FADD). TNFp75R-/- mice showed exacerbated injury and elevated mRNA levels for IL-1α, MIP-1α, and TNFα. In TNFp55R-/- mice, constitutive mRNA levels for TNFα, IL-6, caspase 8, FADD, and Fas-associated phosphatase were higher; IL-1α, MIP-1α, and transforming growth factor β1 lower. The mice displayed exacerbated neuronal death, delayed microglia response, increased FADD and TNFp75R mRNA levels, and co-expression of TNFp75R in AC3⁺ neurons. The data demonstrate TNFR-mediated apoptotic death of dentate granule neurons utilizing both TNFRs and suggest a TNFp75R-mediated apoptosis in the absence of normal TNFp55R activity.