Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue

doi:10.1016/j.neuroscience.2011.02.001

Neuroscience

Volume 179, 14 April 2011, Pages 233-243

https://doi.org/10.1016/j.neuroscience.2011.02.001 Get rights and content

Abstract

Increasing evidence indicates that inflammatory responses could play a critical role in the pathogenesis of motor neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings have underlined the role of Toll-like receptors (TLRs) and the receptor for advanced glycation endproducts (RAGE) in the regulation of both innate and adaptive immunity in different pathologies associated with neuroinflammation. In the present study we investigated the expression and cellular distribution of TLR2, TLR4, RAGE and their endogenous ligand high mobility group box 1 (HMGB1) in the spinal cord of control (n=6) and sporadic ALS (n=12) patients. The immunohistochemical analysis of TLR2, TLR4 and RAGE showed increased expression in reactive glial cells in both gray (ventral horn) and white matter of ALS spinal cord. TLR2 was predominantly detected in cells of the microglia/macrophage lineage, whereas the TLR4 and RAGE was strongly expressed in astrocytes. Real-time quantitative PCR analysis confirmed the increased expression of both TLR2 and TLR4 and HMGB1 mRNA level in ALS patients. In ALS spinal cord, HMGB1 signal is increased in the cytoplasm of reactive glia, indicating a possible release of this molecule from glial cells. Our findings show increased expression of TLR2, TLR4, RAGE and HMGB1 in reactive glia in human ALS spinal cord, suggesting activation of the TLR/RAGE signaling pathways. The activation of these pathways may contribute to the progression of inflammation, resulting in motor neuron injury. In this context, future studies, using animal models, will be important to achieve a better understanding of these signaling pathways in ALS in view of the development of new therapeutic strategies.

Research highlights

▶Increased expression of TLR2, TLR4 and HMGB1 mRNA level in human ALS spinal cord. ▶Increased expression of TLR2, TLR4, RAGE and HMGB1 in reactive glia in ALS spinal cord. ▶Glial cells as major source of extracellular HMGB1 in ALS spinal cord. ▶Our findings suggest activation of the TLR/RAGE signaling pathways in human ALS. ▶HMGB1-TLR/RAGE axis as novel pharmacological target in ALS.

Section snippets

Subjects

Post-mortem material was obtained at autopsy from 12 sporadic ALS patients at the department of Pathology of the Academic Medical Center (University of Amsterdam). All patients fulfilled the diagnostic criteria for sporadic ALS (sALS; El Escorial criteria; Brooks et al., 2000), were reviewed independently by two neuropathologists and the diagnosis of ALS was confirmed according to the standard histopathological criteria (Ince et al., 1998, Piao et al., 2003). The group included six patients

Case material

The clinical and neuropathological characteristics of the subjects are summarized in Table 1. There were no significant differences between the ALS and normal control groups with respect to post-mortem interval or duration of storage. None of the control patients had confounding neurological or neuropathological abnormalities.

Quantitative analysis of TLR2 mRNA expression in ALS spinal cord

Increased TLR2 mRNA expression was observed in both ALS-st and ALS-lt patients, compared to control spinal cord by RT-PCR (Fig. 1A; P<0.05). No significant difference in

Discussion

In the present report we studied the involvement of inflammation in ALS focusing on innate immune mechanisms such as the TLR signaling pathway (Bsibsi et al., 2002, Aravalli et al., 2007, Crack and Bray, 2007, Andersson et al., 2008, Drexler and Foxwell, 2010, Maroso et al., 2010). An up-regulation of TLR 2, TLR4 and HMGB1 expression was demonstrated in specimens of patients with sALS, thus providing direct evidence of a chronic inflammatory state involving the TLR/RAGE pathways in human ALS.

Conclusion

In conclusion, our findings suggest activation of the TLR/RAGE signaling pathways in human ALS. The potential link between TLR/RAGE signaling, progression of inflammation and motoneuron degeneration may suggest new therapeutic strategies, targeting inflammation, to be further explored in ALS.

Acknowledgments

We are grateful to J.T. van Heteren for her technical help. We are grateful to the patients with ALS and their families allowing donation of tissue for research.

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¹: Authors contributed equally to the present work.

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Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperToll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue

Abstract

Research highlights

Section snippets

Subjects

Case material

Quantitative analysis of TLR2 mRNA expression in ALS spinal cord

Discussion

Conclusion

Acknowledgments

Int J Biochem Cell Biol

J Neuroimmunol

Neurobiol Aging

J Biol Chem

Neurosci Lett

Brain Res

Clin Perinatol

Prog Neuropsychopharmacol Biol Psychiatry

Biochim Bioph Acta

Neurosci Lett

Neurobiol Dis

Brain Res

Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis

J Leukoc Biol

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J Neuroimmune Pharmacol

Expression and cell distribution of group I and group II metabotropic glutamate receptor subtypes in taylor-type focal cortical dysplasia

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Expression of brain-derived neurotrophic factor and tyrosine kinase B receptor proteins in glioneuronal tumors from patients with intractable epilepsy: colocalization with N-methyl-d-aspartic acid receptor

Acta Neuropathol

Toll-like receptor 2 signaling in response to brain injury: an innate bridge to neuroinflammation

J Neurosci

HMGB1 loves company

J Leukoc Biol

High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity

Immunol Rev

ImmunologyDangers in and out

Science

Cultured astrocytes express toll-like receptors for bacterial products

Glia

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Amyotroph Lateral Scler Other Motor Neuron Disord

Broad expression of Toll-like receptors in the human central nervous system

J Neuropathol Exp Neurol

tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia

Nat Genet

Differential activation of astrocytes by innate and adaptive immune stimuli

Glia

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Immunol Cell Biol

Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS

Glia

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue