MCP-1/CCR2 signaling-mediated astrocytosis is accelerated in a transgenic mouse model of SOD1-mutated familial ALS.

BACKGROUND

Emerging evidence suggests that innate immunity and increased oxidative stress contribute to pathomechanisms in amyotrophic lateral sclerosis (ALS). The aim of the present study was to verify the involvement of monocyte chemoattractant protein-1 (MCP-1) and its specific CC chemokine receptor 2 (CCR2) in the disease progression of ALS. We here demonstrate the expression state of MCP-1 and CCR2 in lumbar spinal cords of mice overexpressing a transgene for G93A mutant human superoxide dismutase 1 (SOD1) (ALS mice) as a mouse model of ALS as well as the involvement of MCP-1/CCR2-mediated signaling in behavior of cultured astrocytes derived from those mice.

RESULTS

Quantitative polymerase chain reaction analysis revealed that MCP-1 and CCR2 mRNA levels were significantly higher in ALS mice than those in nontransgenic littermates (control mice) at the presymptomatic stage. Immunoblot analysis disclosed a significantly higher CCR2/β-actin optical density ratio in the postsymptomatic ALS mouse group than those in the age-matched control mouse group. Immunohistochemically, MCP-1 determinants were mainly localized in motor neurons, while CCR2 determinants were exclusively localized in reactive astrocytes. Primary cultures of astrocytes derived from ALS mice showed a significant increase in proliferation activity under recombinant murine MCP-1 stimuli as compared to those from control mice.

CONCLUSIONS

Our results provide in vivo and in vitro evidence that MCP-1 stimulates astrocytes via CCR2 to induce astrocytosis in ALS with SOD1 gene mutation. Thus, it is likely that MCP-1/CCR2-mediated sigaling is involved in the disease progression of ALS.