Redox Regulation of the M1/M2 Shift in Microglia: Programming the Deleterious Phenotype

Abstract

Microglia, the resident innate immune cells in the brain, are implicated in the progressive nature of diverse neurodegenerative diseases associated with aging, including Parkinson's disease. Our recent findings point to the loss of NF‐κB p50 function due to reactive oxygen species as a key mechanism driving microglial failure to resolve the M1 (pro‐inflammatory) response and impaired M2 (alternative) activation, where loss of NF‐κB p50 function leads to a CNS‐specific vulnerability to chronic inflammation. Moreover, our current work indicates that aging synergistically augments the brain M1 activation response in NF‐κB p50−/− mice, implicating a role for loss of NF‐κB p50 function in age‐associated microglial priming (heightened sensitivity to pro‐inflammatory stimuli) and dopaminergic neurotoxicity. Together, these findings implicate NF‐κB p50 as pivotal redox signaling mechanism regulating the M1/M2 activation balance in microglia, where loss of function tips this balance to favor a M1 polarized and neurotoxic phenotype. These findings support that loss of NF‐κB p50 function and aging may interact to excessively augment microglial priming and point to a novel pro‐inflammatory signaling mechanism independent the NF‐κB p50/p65 transcription factor in this process.Support or Funding InformationNIEHS/NIH ONES Award R01ES016951; DOD GW120068