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

Hdl Handle:
http://hdl.handle.net/10675.2/621681
Title:
ANTI-INFLAMMATORY ROLE OF 17β-ESTRADIOL IN THE BRAIN
Authors:
Thakkar, Roshni Dinesh
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.
Affiliation:
Department of Neuroscience and Regenerative Medicine
Issue Date:
25-Jan-2018
URI:
http://hdl.handle.net/10675.2/621681
Type:
Dissertation
Description:
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Appears in Collections:
Department of Neuroscience & Regenerative Medicine Theses and Dissertations; Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorThakkar, Roshni Dinesh-
dc.date.accessioned2018-01-25T23:23:33Z-
dc.date.available2018-01-25T23:23:33Z-
dc.date.issued2018-01-25-
dc.identifier.urihttp://hdl.handle.net/10675.2/621681-
dc.descriptionThe file you are attempting to access is currently restricted to Augusta University. Please log in with your NetID if off campus. Record is embargoed until 01/25/2019en
dc.description.abstract17β-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.-
dc.subjectBiological sciencesen
dc.subjectglobal cerebral ischemiaen
dc.subjectNLRP3 inflammasomeen
dc.subjectmicroglia phenotypeen
dc.subjectcytokinesen
dc.subjectneuroprotectionen
dc.titleANTI-INFLAMMATORY ROLE OF 17β-ESTRADIOL IN THE BRAINen
dc.typeDissertationen
dc.contributor.departmentDepartment of Neuroscience and Regenerative Medicineen
dc.language.rfc3066en-
dc.date.updated2018-01-25T23:23:34Z-
dc.description.advisorBrann, Darrellen
dc.description.committeeDhandapani, Krishnan; McCluskey, Lynette; Pillai, Anikumar; Zhang, Quanguangen
dc.description.degreeDoctor of Philosophy with a Major in Molecular Medicineen
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