Long-term stimulation of α7 nicotinic acetylcholine receptor selectively suppresses thrombin-polarized M1 microglia

The effect of nicotine on impaired M1 and protective M2 microglial polarization was investigated using BV-2 cell line. Alpha 7 nicotinic acetylcholine receptor (α7 nAchR) expression was transiently increased by nicotine treatment and then it was gradually decreased for 14 days. Treatment with nicotine for 14 days slightly polarized naïve M0 microglia to CCL1-positive M2b and inducible NO synthase (iNOS)-positive M2d subtypes. Conversely, arginase1-positive M2c microglia was decreased. On the other hand, exposure of thrombin recruited iNOS- and interleukin-1β-double positive M1 microglia. Long-term treatment with nicotine significantly decreased thrombin-induced iNOS mRNA and oppositely showed the tendency to increase the arginase1 mRNA level. From the effect of nicotine on M0 microglia, it is unlikely that nicotine has shifted from iNOS-positive M1 to arginase1-positive M2 subtype. Thus, the selective cell death of M1 microglia was presumed. The mitogen-activated protein kinase (MAPK)s pathway has previously shown to be involved in the survival of thrombin-activated microglia. Treatment with nicotine for 14 days suppressed thrombin-phosphorylated p38 MAPK through the α7 nAchR. These results suggest that long-term stimulation of α7 nAchR causes suppression of thrombin-activated p38 MAPK followed by possible apoptosis in M1 microglia.