Neuronal Damage in Autoimmune Neuroinflammation Mediated by the Death Ligand TRAIL

Aktaş, Orhan; Smorodchenko, Alina; Brocke, Stefan; Infante-Duarte, Carmen; Topphoff, Ulf Schulze; Vogt, Johannes; Prozorovski, Timour; Meier, S.; Osmanova, Venera; Pohl, Elena E.; Bechmann, Ingo; Nitsch, Robert; Zipp, Frauke

doi:10.1016/j.neuron.2005.03.018

Cited by 198 publications

(110 citation statements)

References 63 publications

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“…The roles of these two cytokines in inflammation and apoptosis seem to be variable. Both proteins can induce inflammatory and detrimental effects in brain cells [2,3,50,74]. Nevertheless, both have also been shown to improve neuronal survival under certain circumstances [33,39,65].…”

Section: Discussionmentioning

confidence: 99%

Microglia inflict delayed brain injury after subarachnoid hemorrhage

et al. 2015

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Inflammatory changes have been postulated to contribute to secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH). In human specimens after SAH as well as in experimental SAH using mice, we show an intracerebral accumulation of inflammatory cells between days 4 and 28 after the bleeding. Using bone marrow chimeric mice allowing tracing of all peripherally derived immune cells, we confirm a truly CNS-intrinsic, microglial origin of these immune cells, exhibiting an inflammatory state, and rule out invasion of myeloid cells from the periphery into the brain. Furthermore, we detect secondary neuro-axonal injury throughout the time course of SAH. Since neuronal cell death and microglia accumulation follow a similar time course, we addressed whether the occurrence of activated microglia and neuro-axonal injury upon SAH are causally linked by depleting microglia in vivo. Given that the amount of neuronal cell death was significantly reduced after microglia depletion, we conclude that microglia accumulation inflicts secondary brain injury after SAH.

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Section: Discussionmentioning

confidence: 99%

Microglia inflict delayed brain injury after subarachnoid hemorrhage

et al. 2015

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“…In our study, within 24 h after HI, CD68-positive cells were abundant and activated in the area of the injured hemisphere. Their recruitment has been shown to persist at least 7 days after HI [27,28], and persistent activation of CD68-positive cells may release various cytokines, such as TRAIL, leading to excessive neural cell damage [29]. …”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Ischemia Upregulates TRAIL and TRAIL Receptors in the Immature Rat Brain

et al. 2011

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The immature brain is susceptible to inflammatory injury induced by hypoxia-ischemia (HI) or infection, which causes serious neurodevelopmental disabilities in the survivors of preterm births. Recently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (death receptor DR4/5 and decoy receptor DcR1/2) were reported to mediate various neuroinflammatory responses. However, little information is available regarding the role of TRAIL and its receptors in the immature brain after HI. The purpose of this study was to evaluate the expression of TRAIL and its receptors in the immature brain after HI and relate this expression to neurological function. We performed right common carotid artery ligation followed by hypoxia (6% O₂, 37°C) for 2.5 h to induce HI in postnatal day 3 rats. The distribution of TRAIL and its receptors, caspase-3 and CD68-labeled microglia/macrophages was evaluated 24 h after HI by immunostaining. The protein and mRNA expression of TRAIL and DR5 was measured by Western blot and real-time PCR, respectively. Delayed neuronal loss was evaluated by NeuN and Nissl staining 7 days after HI. Furthermore, neurological deficits were evaluated by a righting reflex test, time of eye opening and T-maze test. The expression of TRAIL, DR5 and DcR1/2 receptors and caspase-3 was more pronounced in the ipsilateral hemisphere compared with the contralateral part and the control group 24 h after HI. DR5/active caspase-3 double-positive cells were observed at 24 h after HI in the ipsilateral hemisphere but not in the contralateral hemisphere. The TRAIL and CD68 double-labeled cells were more pronounced in the ipsilateral cortical regions compared with the corresponding regions of the contralateral part. HI also resulted in a significant increase in TRAIL and DR5 protein and mRNA expression at 24 h, which corresponded to neuronal cell loss 7 days after HI. Furthermore, the HI group displayed impaired neurobehavioral development compared with the control group (p < 0.05). Altogether our results show that the TNF-α superfamily ligand TRAIL is induced on CD68+ microglia/macrophages after perinatal HI and that one of its receptors, DR5, is induced on neocortical neurons and glial cells. That many DR5+ cells were also caspase-3+ strongly supports the conclusion that these signaling molecules are involved in the delayed loss of neurons in the neocortex and in the neurobehavioral deficits that are often seen after perinatal HI.

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“…These apoptotic proteins can be activated by tumor necrosis factor, released from pro-inflammatory T cells in multiple sclerosis lesions, and have been demonstrated to promote oligodendrocyte cell death in vitro [5,13]. Blockade of these proteins has been demonstrated to protect against experimental autoimmune encephalitis in animals [1,20]. Finally, injury to the myelin sheath may render oligodendrocytes vulnerable to environmental toxins or viruses.…”

Section: Mechanisms Of Demyelinationmentioning

confidence: 99%

The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage

2005

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Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system manifested morphologically by inflammation, demyelination, axonal loss and gliosis. The inflammatory lesions are characterized by massive infiltration by a heterogeneous population of cellular and soluble mediators of the immune system, including T cells, B cells, macrophages and mi croglia, as well as a broad range of cytokines, chemokines, antibodies, complement and other toxic substances. The appearance of such lesions is associated with clinical relapses. Recent detailed immunopathological studies of early, acute lesions revealed profound heterogeneity in the patterns of demyelination and the factors of the immune system involved. During remission, resolution of inflammation is the main factor which leads to clinical improvement of patients. However, the immune system can play a beneficial role at this stage, promoting remyelination perhaps by production of growth factors such as BDNF. In contrast, the progressive irreversible neurological deficit in multiple sclerosis is associated with neurodegenerative processes resulting in axonal and neuronal loss. The mechanisms behind damage to axons in multiple sclerosis lesions are poorly understood. However, the close proximity of areas with prominent axonal loss and areas containing inflammatory infiltrates (e. g., T cells, macrophages) suggest that axonal damage is closely associated with inflammation. Different soluble or cellular mediators of the immune response have been shown to damage axons in experimental systems, and these may be responsible for neurodegeneration in human disease.

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Neuronal Damage in Autoimmune Neuroinflammation Mediated by the Death Ligand TRAIL

Cited by 198 publications

References 63 publications

Microglia inflict delayed brain injury after subarachnoid hemorrhage

Microglia inflict delayed brain injury after subarachnoid hemorrhage

Hypoxia-Ischemia Upregulates TRAIL and TRAIL Receptors in the Immature Rat Brain

The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage

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