Abstract
Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we characterized both the proinflammatory and neurotoxic effects of TLR4 activation with lipopolysaccharide (activation of microglial cells, release of proinflammatory cytokines and motor neuron death) and the protective effects of a cyanobacteria-derived TLR4 antagonist (VB3323). With the use of TLR4-deficient cells, a critical role of the microglial component with functionally active TLR4 emerged in this setting. The in vivo experiments were carried out in a mouse model of spontaneous motor neuron degeneration, the wobbler mouse, where we preliminarily confirmed a protective effect of TLR4 antagonism. Compared with vehicle- and riluzole-treated mice, those chronically treated with VB3323 showed a decrease in microglial activation and morphological alterations of spinal cord neurons and a better performance in the paw abnormality and grip-strength tests. Taken together, our data add new understanding of the role of TLR4 in mediating neurotoxicity in the spinal cord and suggest that TLR4 antagonists could be considered in future studies as candidate protective agents for motor neurons in degenerative diseases.
Highlights
In pathological conditions, persistent immune-stimulating signals may induce aberrant microglial activation with elevated cytokine release, eventually leading to neuronal injury
By using primary spinal cord cultures from mouse embryos as an in vitro model for the study of motor neuron injuries, we investigated the effects induced by Toll-like receptor 4 (TLR4) activation in neurons and glial cells
Distribution of TLR4 in Spinal Cord Cells In a first set of experiments, TLR4 expression was analyzed in the resident cell types of the spinal cord
Summary
Persistent immune-stimulating signals may induce aberrant microglial activation with elevated cytokine release, eventually leading to neuronal injury. Toll-like receptors (TLRs) recognize highly conserved structural motifs from either pathogens or damaged and stressed tissues and are involved in microglial response to physiological and pathological signals. A well-known natural ligand of TLR4 is endotoxin/lipopolysaccharide (LPS), one of the major cell wall components of Gram-negative bacteria [6]. LPS has potent immunostimulatory effects [7], mainly exerted through TLR4/MD2/ CD14-bearing cells [8,9]. The membrane anchor of LPS is a glucosamine-based phospholipid called lipid A, which represents the endotoxic principle of LPS and is responsible for its pathophysiological effects [10] via TLR4 [11,12]. There is convincing evidence that LPS/TLR4 signaling is involved in various human and experimental central nervous system (CNS) diseases. Altered levels of the receptor have been reported in brain
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