Soluble TNF receptors partially protect injured motoneurons in the postnatal CNS

Abstract

There is accumulating evidence that cytokines are involved in the functioning of the brain and the spinal cord. However, it has been controversial whether they exert a neurotoxic or a neuroprotective effect. To address this question in vivo, we have examined the survival of injured motoneurons in a line of transgenic mice that overexpress the soluble form of tumour necrosis factor receptor-1 (sTNFR1). In these animals, all of the circulating TNF and lymphotoxin-alpha are neutralized by the continuous expression of the soluble receptor. Following axotomy of the facial nerve in 7-day-old control mice, we observed a loss of approximately 90% of the motoneurons at two weeks survival. In the transgenic mice under the same conditions, the percentage of motoneuron survival was increased two-fold (515 vs. 224) and varied as a function of the level of the circulating receptor. These results indicate that neutralization of endogenous TNF and lymphotoxin-alpha by means of overexpression of the soluble receptor can decrease cell death of injured motoneurons and suggest that these cytokines may play an important role in neuronal degeneration in the CNS following a lesion.

Effects of TNF-α and IFN-γ on Nitric Oxide-Induced Neurotoxicity in the Mouse Brain

“…They have also observed a better cell survival in animals treated with a NO synthesis inhibitor. Besides, constitutive production of soluble TNF-␣ type I receptor in transgenic mice significantly inhibited the neurodegenerative events following motoneuron axotomy (27). Moreover, this cytokine plays a critical role in the profound neurodegeneration taking place in animals treated with the glucocorticoid receptor inhibitor RU486 before the intrastriatal bolus of LPS (28).…”

Concomitant rheumatoid arthritis and amyotrophic lateral sclerosis: report of two new cases and review of literature

“…On other hand, it seems to be not essential for the induction of disease but may limits the evolution in a second time of its history. These two contradictory effects can perhaps be explained by the activation of two different receptors, TNFR1 for neurotoxic effect and TNFR2 for neurotrophic [41][42][43][44][45]. Surprisingly, when these concepts were transferred on clinical point of view and anti-TNFa antibodies were finally tested in MS patients, any clinically significant changes were noted, instead the number of magnetic resonance lesions increased after each treatment and the disease worsened [46].…”

Absence of Tumor Necrosis Factor-α Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutations

“…TNF-␣ is one of the most potent proinflammatory cytokine and is capable of activating microglia and causing neurotoxicity in systems in which the neuronal population has been compromised (Robertson et al, 2001;Zou and Crews, 2005). Furthermore, neutralization of TNF-␣ can reduce neuronal damage (Terrado et al, 2000), and TNF-␣ is able to mediate motor neuron cell death in certain experimental paradigms (He et al, 2002). Interestingly, administration of thalidomide, a potent antiinflammatory and immunomodulatory drug, whose effects include inhibition of TNF-␣ synthesis, delays death in SOD1 G93A mice (Kiaei et al, 2006).…”

“…Production of TNF-␣ is closely associated with disease progression in SOD1 transgenic mice (Elliott, 2001;Hensley et al, 2003), and several studies have designated TNF-␣ as a pathogenic mediator in many CNS diseases with an inflammatory component (Ghezzi and Mennini, 2001;Viviani et al, 2004). Although TNF-␣ can mediate motor neuron death (Terrado et al, 2000;Robertson et al, 2001;He et al, 2002), its role in disease pathogenesis mediated by SOD1 mutants remains unclear. Here, to elucidate the contribution of TNF-␣ to the neurodegenerative processes in ALS caused by SOD1 mutations, we generated mice overexpressing SOD1 G37R or SOD1…”