Absence of toll-like receptor 4 (TLR4) extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis

Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a devastating late onset neurodegenerative disorder that is characterised by the progressive loss of upper and lower motor neurons. The mechanisms underlying ALS pathogenesis are unclear; however, there is emerging evidence the innate immune system, including components of the toll-like receptor (TLR) system, may drive disease progression. For example, toll-like receptor 4 (TLR4) antagonism in a spontaneous ‘wobbler mouse’ model of ALS increased motor function, associated with a decrease in microglial activation. This study therefore aimed to extend from these findings and determine the expression and function of TLR4 signalling in hSOD1G93A mice, the most widely established preclinical model of ALS.FindingsTLR4 and one of its major endogenous ligands, high-mobility group box 1 (HMGB1), were increased during disease progression in hSOD1G93A mice, with TLR4 and HMGB1 expressed by activated microglia and astrocytes. hSOD1G93A mice lacking TLR4 showed transient improvements in hind-limb grip strength and significantly extended survival when compared to TLR4-sufficient hSOD1G93A mice.ConclusionThese results suggest that enhanced glial TLR4 signalling during disease progression contributes to end-stage ALS pathology in hSOD1G93A mice.

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis

“…The present study clearly demonstrated a marked reduction in overall inflammatory markers in the spinal cord including decreases in pro-inflammatory cytokines TNF α and IL-1β, the RAGE ligand and danger-associated molecular pattern molecule HMGB1, innate immune receptors TLR4 and C5aR1, inflammasome component NLRP3, and an oxidative stress marker. This is consistent with many prior studies demonstrating these components play pathogenic roles in ALS disease progression [35,36,40-43,20,19,37,44]. Interestingly, genetic deletion of RAGE also resulted in a down-regulation of the complement components C1qb and C3.…”

“…It is now well documented that RAGE and its pro-inflammatory ligands are potentially involved in ALS, with evidence from both human patients and rodent models [6,10,11,13,20,19,12]. The present study further adds to this knowledge demonstrating alteration of RAGE mRNA expression in the spinal cord and skeletal muscle of multiple preclinical transgenic ALS mouse models including SOD1 G93A , TDP43 Q331K and TDP43 WTxQ331K mice, suggestive of a common activation pathway for RAGE upregulation in these models, that is independent to the underlying genetic driver of the disease.…”

Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes

“…Similarly, deficiency of CD14 had no effect on the survival time of SOD1 G93A mice [24]. On the other hand, TLR4 deficiency prolonged the survival of SOD1 G93A mice [25]. Since TLR4 activates both MyD88-dependent and TRIF-dependent signaling pathways, the individual contributions of these pathways remain unclear.…”

Neuroinflammation in motor neuron disease

“…16 Gene ablation of TLR4 in SOD1 mice slightly extended survival ( Table 1). 17 In contrast, eliminating myeloid differentiation factor 88, an essential adaptor protein responsible for most of the TLR signaling pathways except TLR3, in SOD1 mice showed no effect on survival times (Table 1). 18 Understanding the roles of innate immunity including myeloid differentiation factor 88-dependent pathway and TIR-domain-containing adapter-inducing interferon-b-dependent pathway in ALS requires further investigation.…”

“…Expression levels of TLR2 and TLR4 are upregulated in the spinal cord of not only SOD1 mice, but also patients with ALS, and TLR2 is expressed predominantly in microglia, whereas TLR4 is expressed mainly in astrocytes . Gene ablation of TLR4 in SOD1 mice slightly extended survival (Table ) . In contrast, eliminating myeloid differentiation factor 88, an essential adaptor protein responsible for most of the TLR signaling pathways except TLR3, in SOD1 mice showed no effect on survival times (Table ) .…”