Tumor necrosis factor alpha and interferon gamma cooperatively induce oxidative stress and motoneuron death in rat spinal cord embryonic explants

Mir, Margalida; Asensio, Víctor J.; Tolosa, Laia; Gou-Fàbregas, Myriam; Soler, Rosa M.; Lladó, Jerònia; Olmos, Gabriel

doi:10.1016/j.neuroscience.2009.05.049

Cited by 51 publications

(45 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, it has been shown that exposure of freshly isolated motoneurons to IFNg fails to alter neuron survival. 33 In our survival experiments, motoneurons were cultured for at least 24 h before treatment and indeed we observed that freshly isolated motoneurons were resistant to IFNg or LIGHT (not shown), suggesting that motoneurons need at least 24 h to acquire competence to die through IFNg and LIGHT. In the light of these studies, IFNg can be proposed as a key player of toxicity of mutant astrocytes by directly promoting death of motoneurons through LIGHT and by promoting release of other glialderived neurotoxic factors.…”

Section: Discussionmentioning

confidence: 71%

IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

et al. 2010

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that primarily affects motoneurons in the brain and spinal cord. Dominant mutations in superoxide dismutase-1 (SOD1) cause a familial form of ALS. Mutant SOD1-damaged glial cells contribute to ALS pathogenesis by releasing neurotoxic factors, but the mechanistic basis of the motoneuron-specific elimination is poorly understood. Here, we describe a motoneuron-selective death pathway triggered by activation of lymphotoxin-b receptor (LT-bR) by LIGHT, and operating by a novel signaling scheme. We show that astrocytes expressing mutant SOD1 mediate the selective death of motoneurons through the proinflammatory cytokine interferon-c (IFNc), which activates the LIGHT-LT-bR death pathway. The expression of LIGHT and LT-bR by motoneurons in vivo correlates with the preferential expression of IFNc by motoneurons and astrocytes at disease onset and symptomatic stage in ALS mice. Importantly, the genetic ablation of Light in an ALS mouse model retards progression, but not onset, of the disease and increases lifespan. We propose that IFNc contributes to a cross-talk between motoneurons and astrocytes causing the selective loss of some motoneurons following activation of the LIGHT-induced death pathway.

show abstract

Section: Discussionmentioning

confidence: 71%

IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

et al. 2010

View full text Add to dashboard Cite

show abstract

“…It has been shown that treatment of SC explant cultures with TNF-␣ and IFN-␥ increases inducible nitric oxide synthase (iNOS) expression in microglia and apoptosis of motor neurons (52). We have previously shown that iNOS is upregulated in reovirus-induced encephalitis and myelitis (29,30).…”

Section: Discussionmentioning

confidence: 99%

Activation of Innate Immune Responses in the Central Nervous System during Reovirus Myelitis

Schittone

Dionne²,

Tyler³

et al. 2012

J Virol

View full text Add to dashboard Cite

f Reovirus infection of the murine spinal cord (SC) was used as a model system to investigate innate immune responses during viral myelitis, including the activation of glia (microglia and astrocytes) and interferon (IFN) signaling and increased expression of inflammatory mediators. Reovirus myelitis was associated with the pronounced activation of SC glia, as evidenced by characteristic changes in cellular morphology and increased expression of astrocyte and microglia-specific proteins. Expression of inflammatory mediators known to be released by activated glia, including interleukin-1␤ (IL-1␤), tumor necrosis factor alpha (TNF-␣), chemokine (C-C motif) ligand 5 (CCL 5), chemokine (C-X-C motif) ligand 10 (CXCL10), and gamma interferon (IFN-␥), was also significantly upregulated in the SC of reovirus-infected animals compared to mock-infected controls. Reovirus infection of the mouse SC was also associated with increased expression of genes involved in IFN signaling, including IFN-stimulated genes (ISG). Further, reovirus infection of mice deficient in the expression of the IFN-␣/␤ receptor (IFNAR ؊/؊ ) resulted in accelerated mortality, demonstrating that IFN signaling is protective during reovirus myelitis. Experiments performed in ex vivo SC slice cultures (SCSC) confirmed that resident SC cells contribute to the production of at least some of these inflammatory mediators and ISG during reovirus infection. Microglia, but not astrocytes, were still activated, and glia-associated inflammatory mediators were still produced in reovirus-infected INFAR ؊/؊ mice, demonstrating that IFN signaling is not absolutely required for these neuroinflammatory responses. Our results suggest that activated glia and inflammatory mediators contribute to a local microenvironment that is deleterious to neuronal survival.

show abstract

“…For example, TNFα and IFNγ can operate through PKC and the NFκB transcription factor to induce gp91 PHOX expression [26,27]. T-cell derived cytokines, such as interleukin-17A, can also induce NADPH oxidase activity [28].…”

Section: Nadph Oxidasementioning

confidence: 99%

“…A recent study by Hur et al [31] further demonstrated that microglia exposed to ischemia induced neuronal cell apoptosis, which could be blocked by knocking out gp91 PHOX . Furthermore, addition of TNFα and interleukin-1β to spinal cord explants resulted in NADPH oxidase activity and 3-nitrotyrosine (3-NT) accumulation in spinal cord motoneurons, but only when microglia were present [26].…”

Section: Nadph Oxidasementioning

confidence: 99%

Novel Neuroinflammatory Targets in the Chronically Injured Spinal Cord

Pajoohesh‐Ganji

Byrnes

2011

Neurotherapeutics

View full text Add to dashboard Cite

Summary: Injury to the spinal cord is known to result in inflammation. To date, the preponderance of research has focused on the acute neuroinflammatory response, which begins immediately and is believed to terminate within hours to (at most) days after the injury. However, recent studies have demonstrated that postinjury inflammation is not restricted to the first few hours or days after injury, but can last for months to years after a spinal cord injury (SCI). These chronic studies have revealed that increased numbers of inflammatory cells, such as microglia and macrophages, and inflammatory factors, including cytokines, chemokines, and enzyme products are found at markedly delayed times after injury. Here we review experimental work on a selection of the novel inflammatory factors observed chronically after SCI, including the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase enzyme and galectin-3. We will discuss the role of these proteins in inflammation with regard to both detrimental and beneficial effects of neuroinflammation after injury. Finally, the potential of these proteins to serve as therapeutic targets will be considered, and a novel therapeutic approach (i.e., the agonist for metabotropic glutamate receptor 5 [mGluR5], [RS]-2-Chloro-5-hydroxyphenylglycine [CHPG]) will be discussed. This review will demonstrate the expression and activity profiles, roles in potentiation of injury, and therapy studies of these inflammatory factors suggest that not only are these chronically expressed factors viable targets for SCI treatment, but that the therapeutic window is broader than has previously been thought.

show abstract

Tumor necrosis factor alpha and interferon gamma cooperatively induce oxidative stress and motoneuron death in rat spinal cord embryonic explants

Cited by 51 publications

References 70 publications

IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

Activation of Innate Immune Responses in the Central Nervous System during Reovirus Myelitis

Novel Neuroinflammatory Targets in the Chronically Injured Spinal Cord

Contact Info

Product

Resources

About