ANTI-INFLAMMATORY ROLE OF 17β-ESTRADIOL IN THE BRAIN

Abstract

17β-estradiol (E2) is a well-known neuroprotective hormone, but its role in regulation of neuroinflammation is less understood. In the current study, we examined whether E2, acting via PELP1, can exert anti-inflammatory effects in the ovariectomized rat and mouse hippocampus to regulate NLRP3 inflammasome activation, cytokine production and microglial M1/M2 phenotype after global cerebral ischemia (GCI). The results showed that activation of the NLRP3 inflammasome pathway and expression of its downstream products, cleaved caspase-1, and IL-1β, are temporally increased in the hippocampus after GCI, with peak levels observed at 6-7 days. E2 robustly inhibited NLRP3 inflammasome pathway activation, caspase-1 and pro-inflammatory cytokine production, as well as gliosis after GCI at gene as well as protein levels. Moreover, E2 also profoundly suppressed the pro-inflammatory M1 microglial phenotype, while increasing the anti-inflammatory M2 microglial phenotype after GCI. Intriguingly, the ability of E2 to exert all of these anti-inflammatory effects was lost in PELP1 forebrain-specific knockout mice. These robust effects of E2 may be mediated directly upon microglia, as we found that E2 suppressed the M1 while enhancing the M2 microglia phenotype in LPS-activated BV2 microglia cells. Furthermore, E2 treatment also prevented the neurotoxic effects of BV2 microglia cells upon hippocampal HT-22 neurons, suggesting a novel E2-mediated neuroprotective effect via regulation of microglia activation and phenotype. Mechanistically, E2 strongly suppressed expression and activation of the transcription factor NF-κB in BV2 microglia cells, which is known to be a critical regulator of both microglia pro-inflammatory effects and M1/M2 microglia phenotype. Additional studies revealed that NF-κB inhibition also prevents the cytotoxic effects of BV2 microglia cells upon hippocampal HT-22 neurons. Collectively, our study suggests a novel E2-mediated neuroprotective effect via regulation of inflammasome and microglia activation and promotion of the M2 “anti-inflammatory” phenotype in the brain. KEY WORDS: Estrogen, global cerebral ischemia, NLRP3 inflammasome, microglia phenotype, cytokines, neuroprotection.