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Dynamic impact of brief electrical nerve stimulation on the neural immune axis—polarization of macrophages toward a pro‐repair phenotype in demyelinated peripheral nerve
Author(s) -
M Nikki A.,
Verge Valerie M. K.
Publication year - 2016
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23021
Subject(s) - remyelination , immune system , biology , phenotype , stimulation , chemokine , sciatic nerve , peripheral nervous system , axon , immunology , macrophage polarization , microbiology and biotechnology , pathology , neuroscience , myelin , central nervous system , medicine , anatomy , gene , biochemistry
Demyelinating peripheral nerves are infiltrated by cells of the monocyte lineage, including macrophages, which are highly plastic, existing on a continuum from pro‐inflammatory M1 to pro‐repair M2 phenotypic states. Whether one can therapeutically manipulate demyelinated peripheral nerves to promote a pro‐repair M2 phenotype remains to be elucidated. We previously identified brief electrical nerve stimulation (ES) as therapeutically beneficial for remyelination, benefits which include accelerated clearance of macrophages, making us theorize that ES alters the local immune response. Thus, the impact of ES on the immune microenvironment in the zone of demyelination was examined. Adult male rat tibial nerves were focally demyelinated via 1% lysophosphatidyl choline (LPC) injection. Five days later, half underwent 1 hour 20 Hz sciatic nerve ES proximal to the LPC injection site. ES had a remarkable and significant impact, shifting the macrophage phenotype from predominantly pro‐inflammatory/M1 toward a predominantly pro‐repair/M2 one, as evidenced by an increased incidence of expression of M2‐associated phenotypic markers in identified macrophages and a decrease in M1‐associated marker expression. This was discernible at 3 days post‐ES (8 days post‐LPC) and continued at the 5 day post‐ES (10 days post‐LPC) time point examined. ES also affected chemokine (C‐C motif) ligand 2 (CCL2; aka MCP‐1) expression in a manner that correlated with increases and decreases in macrophage numbers observed in the demyelination zone. The data establish that briefly increasing neuronal activity favorably alters the immune microenvironment in demyelinated nerve, rapidly polarizing macrophages toward a pro‐repair phenotype, a beneficial therapeutic concept that may extend to other pathologies. GLIA 2016;64:1546–1561