Neurodegeneration in autoimmune CNS inflammation

doi:10.1016/j.expneurol.2009.11.019

Experimental Neurology

Volume 225, Issue 1, September 2010, Pages 9-17

https://doi.org/10.1016/j.expneurol.2009.11.019 Get rights and content

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, in which the myelin sheath has been considered to be the primary target for many years. However, an increasing number of reports have focused on neurodegenerative aspects of the disease pathogenesis. Recent studies in post-mortem MS biopsies and in the animal model Experimental Autoimmune Encephalomyelitis (EAE) have shown that key features of neurodegeneration, i.e. axonal transection, neuronal cell atrophy and neuronal death already occur in early disease phases. Furthermore, it has become clear that irreversible disability correlates stronger with the neuronal affectation than with demyelination. However the cause of neuronal damage still remains elusive, since both demyelination-dependent and direct immune cell-mediated mechanisms have been suggested so far. Here, we summarize the current concepts and recently identified molecular mechanisms of inflammatory neurodegeneration in autoimmune CNS inflammation and highlight the role of different immune cells in the complex network of interactions leading to neuronal damage.

Section snippets

Multiple Sclerosis — current concepts of inflammatory neurodegeneration

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS), and the major cause of neurological disability in young adults. The disseminated CNS lesions cause a plethora of clinical neurological defects in the motor, sensory, visual and autonomous nervous system. The most frequent symptoms are weakness in one or more limbs, sensory disturbances, optic neuritis, ataxia, bladder dysfunction, fatigue and cognitive deficits (O'Connor, 2002). The

Lessons from the animal model of MS

Due to the limited availability of human brain tissue during active disease, especially in early disease stages, a broad variety of rodent animal models have been developed to get a deeper understanding of the molecular mechanisms and kinetics of neuronal cell death and axonal degeneration during inflammatory autoimmune CNS disease. EAE can be induced in certain rodent strains, either by active immunization with myelin proteins/peptides (active EAE) or by transfer of myelin-specific

Axonal degeneration as a consequence of demyelination

According to current concepts, which are mainly based on evidence from animal models, myelin-specific T cells are activated outside the CNS, followed by upregulation of adhesion molecules and chemokine receptors, allowing them to adhere, role along and finally transmigrate through the endothelium (Charo and Ransohoff, 2006, Engelhardt and Ransohoff, 2005). Once in the perivascular space, autoreactive T cells get reactivated by local antigen-presenting cells, such as dendritic cells (Greter et

Immune cell-mediated axonal injury and neuronal cell death

Besides demyelination, inflammation is critical for neuronal damage due to bystander damage by proinflammatory neurotoxic substances and due to direct damage processes, which involve cell contact-dependent mechanisms (Fig. 1). The inflammatory infiltrates of active and chronic active MS and EAE lesions consist mainly of CD4+ T cells, CD8+ T cells and activated microglia/macrophages (Ferguson et al., 1997, Traugott et al., 1983).

Neuroprotective approaches to state-of-the art MS treatment

The novel insights to our understanding of neurodegenerative aspects in EAE and MS, as outlined above, indicate that future therapeutic strategies should focus on inhibition of axonal degeneration and on protection against neuronal cell death additionally to conventional immune modulation. First, promising treatment strategies with a combination of immune-modulatory and neuroprotective drugs include the modulation of cannabinoid receptor activation (Maresz et al., 2007, Zhang et al., 2009) as

Concluding remarks

In summary, it is evident that inflammation-induced demyelination is a crucial prerequisite for axonal degeneration, leading to metabolic dysfunction and a higher vulnerability of unprotected axons to soluble and diffusible neurotoxic mediators of invading inflammatory cells. However, the question remains: how can we explain signs of complete neuronal loss and cell death observed at the very early stages of disease? With regard to this question, research focus has shifted to the involvement of

Acknowledgments

We thank Lena Mann for helpful comments on the manuscript as a native English speaker. Frauke Zipp received grants from the Deutsche Forschungsgemeinschaft (DFG) (SFB 650, SFB-TRR 43 to FZ; GRK1258 to JH).

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ReviewNeurodegeneration in autoimmune CNS inflammation

Abstract

Section snippets

Multiple Sclerosis — current concepts of inflammatory neurodegeneration

Lessons from the animal model of MS

Axonal degeneration as a consequence of demyelination

Immune cell-mediated axonal injury and neuronal cell death

Neuroprotective approaches to state-of-the art MS treatment

Concluding remarks

Acknowledgments

Neuron

Mol. Cell Neurosci.

Brain Res.

Free Radic. Biol. Med.

Brain Behav. Immun.

Neuroimage

Lancet

Immunity

J. Neuroimmunol.

Cytokine

Trends Immunol

Brain Res. Brain Res. Rev.

Brain Res. Brain Res. Rev.

Brain Res.

J. Neuroimmunol.

Neurobiol. Dis.

Neuroscience

Am. J. Pathol.

Am. J. Pathol.

Lancet Neurol

Neuroimage

Lancet

Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis

J. Immunol.

The role of TRAIL/TRAIL receptors in central nervous system pathology

Front. Biosci.

Interleukin-1 and neuronal injury

Nat. Rev. Immunol.

Regulatory T cells in the control of inflammatory demyelinating diseases of the central nervous system

Curr. Opin. Neurol.

Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke

Neuropathol. Appl. Neurobiol.

Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion

Ann. Neurol.

Circulating monocytic cells infiltrate layers of anterograde axonal degeneration where they transform into microglia

FASEB J.

Axonal protection using flecainide in experimental autoimmune encephalomyelitis

Ann. Neurol.

Axonal protection achieved in a model of multiple sclerosis using lamotrigine

J. Neurol.

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J. Clin. Invest.

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Brain

Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients

Ann. Neurol.

Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration

Mult. Scler.

Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease

J. Clin. Invest.

Cortical atrophy is relevant in multiple sclerosis at clinical onset

J. Neurol.

Intra-parenchymal injection of tumor necrosis factor-alpha and interleukin 1-beta produces dopamine neuron loss in the rat

J. Neural Transm.

The many roles of chemokines and chemokine receptors in inflammation

N. Engl. J. Med.

Using co-cultures expressing fluorescence resonance energy transfer based protein biosensors to simultaneously image caspase-3 and Ca2+ signaling

Biotechnol. Lett.

Sodium channels contribute to microglia/macrophage activation and function in EAE and MS

Glia

The contribution of demyelination to axonal loss in multiple sclerosis

Brain

Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study

Brain

Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage

J. Exp. Med.

Lack of tumor necrosis factor-related apoptosis-inducing ligand but presence of its receptors in the human brain

J. Neurosci.

Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients

Ann. Neurol.

Review
Neurodegeneration in autoimmune CNS inflammation