NLRP3 Inflammasome Activation in the Brain after Global Cerebral Ischemia and Regulation by 17 β -Estradiol

Roshni Thakkar, Ruimin Wang, Gangadhara Sareddy, Jing Wang, Dharma Thiruvaiyaru, Ratna Vadlamudi, Quanguang Zhang, Darrell Brann

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

17β-Estradiol (E2) is a well-known neuroprotective factor in the brain. Recently, our lab demonstrated that the neuroprotective and cognitive effects of E2 require mediation by the estrogen receptor (ER) coregulator protein and proline-, glutamic acid-, and leucine-rich protein 1 (PELP1). 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 after global cerebral ischemia (GCI). Activation of the NLRP3 inflammasome pathway and expression of its downstream products, cleaved caspase-1 and IL-1β, were robustly increased in the hippocampus after GCI, with peak levels observed at 6-7 days. Expression of P2X7 receptor, an upstream regulator of NLRP3, was also increased after GCI. E2 markedly inhibited NLRP3 inflammasome pathway activation, caspase-1, and proinflammatory cytokine production, as well as P2X7 receptor expression after GCI (at both the mRNA and protein level). Intriguingly, the ability of E2 to exert these anti-inflammatory effects was lost in PELP1 forebrain-specific knockout mice, indicating a key role for PELP1 in E2 anti-inflammatory signaling. Collectively, our study demonstrates that NLRP3 inflammasome activation and proinflammatory cytokine production are markedly increased in the hippocampus after GCI, and that E2 signaling via PELP1 can profoundly inhibit these proinflammatory effects.

Original languageEnglish (US)
Article number8309031
JournalOxidative medicine and cellular longevity
Volume2016
DOIs
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Biochemistry
  • Aging
  • Cell Biology

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