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

Abstract

BackgroundEmerging 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.ResultsQuantitative 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.ConclusionsOur 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.

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

“…CCR2 and its ligand monocyte chemoattractant protein-1 (MCP-1) play a role in the macrophage inflammatory response following PNS injury, and promote nerve regeneration40. CCR2 and MCP-1 have previously been reported to be implicated in both ALS41 and peripheral neuropathies pathogenetic cascade42. Our finding corroborates the hypothesis that defective monocyte/macrophages infiltration at the site of nerve degeneration may be implicated in ALS.…”

Repeated Intrathecal Mesenchymal Stem Cells for Amyotrophic Lateral Sclerosis

“…Between December 5, 2011 and November 22, 2012, a total of 71 participants with ALS were screened, of whom 7 were excluded (see Fig 1B). Of the remaining 64 participants (mean age = 53.3 years; 33 men and 31 women), 33 were allocated to receive BM-MSCs with riluzole treatment (MSC group) and 31 received riluzole alone (control group). A total of 59 participants at 4 months and 56 participants at 6 months were included in the primary efficacy analysis (full analysis set).…”

Endotoxemia-induced cytokine-mediated responses of hippocampal astrocytes transmitted by cells of the brain–immune interface

“…Although CCL2, CXCL1, and CXCL2 are in the chemokine family, functions of these cytokines are not considered to be related to chemoattraction in this case because astrocytes are unlikely to be chemoattracted. It has been reported that astrocytes can express CCR2 26 and CXCR2 27 as well as IL-6R 28 , and can exert specific functions via these receptors. Activated astrocytes can release CCL11 29 and G-CSF 30 .…”