Exp Mol Med.  2014 Apr;46(4):e91. 10.1038/emm.2014.6.

beta1-integrin-dependent migration of microglia in response to neuron-released alpha-synuclein

• Kim C
• Cho ED
• Kim HK
• You S
• Lee HJ
• Hwang D
• Lee SJ

• KMID: 2155356
• DOI: http://doi.org/10.1038/emm.2014.6

Abstract

Chronic neuroinflammation is an integral pathological feature of major neurodegenerative diseases. The recruitment of microglia to affected brain regions and the activation of these cells are the major events leading to disease-associated neuroinflammation. In a previous study, we showed that neuron-released alpha-synuclein can activate microglia through activating the Toll-like receptor 2 (TLR2) pathway, resulting in proinflammatory responses. However, it is not clear whether other signaling pathways are involved in the migration and activation of microglia in response to neuron-released alpha-synuclein. In the current study, we demonstrated that TLR2 activation is not sufficient for all of the changes manifested by microglia in response to neuron-released alpha-synuclein. Specifically, the migration of and morphological changes in microglia, triggered by neuron-released alpha-synuclein, did not require the activation of TLR2, whereas increased proliferation and production of cytokines were strictly under the control of TLR2. Construction of a hypothetical signaling network using computational tools and experimental validation with various peptide inhibitors showed that beta1-integrin was necessary for both the morphological changes and the migration. However, neither proliferation nor cytokine production by microglia was dependent on the activation of beta1-integrin. These results suggest that beta1-integrin signaling is specifically responsible for the recruitment of microglia to the disease-affected brain regions, where neurons most likely release relatively high levels of alpha-synuclein.

Keyword

alpha-synuclein; beta1-integrin; microglial migration; neuroinflammation; Parkinson's disease

MeSH Terms

Animals
Antigens, CD29/genetics/*metabolism
Cell Line, Tumor
*Cell Movement
Cells, Cultured
Culture Media, Conditioned/*pharmacology
Gene Regulatory Networks
Humans
Mice
Mice, Inbred C57BL
Microglia/drug effects/metabolism/*physiology
Neurons/*metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction
Toll-Like Receptor 2/metabolism
alpha-Synuclein/*pharmacology
Antigens, CD29
Culture Media, Conditioned
Toll-Like Receptor 2
alpha-Synuclein