HIV-1 tat primes and activates microglial NLRP3 inflammasome-mediated neuroinflammation

Ernest T. Chivero, Minglei Guo, Palsamy Periyasamy, Ke Liao, Shannon E. Callen, Shilpa J Buch

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Neuroinflammation associated with HIV-1 infection is a problem affecting <50% of HIV-infected individuals. NLR family pyrin domain containing 3 (NLRP3) inflammasome has been implicated in HIV-induced microglial activation, but the mechanism(s) remain unclear. Because HIV-1 Transactivator of Transcription (Tat) protein continues to be present despite antiretroviral therapy and activates NF-kB, we hypothesized that Tat could prime the NLRP3 inflammasome. We found a dose- and time-dependent induction of NLRP3 expression in microglia exposed to Tat compared with control. Tat exposure also time-dependently increased the mature caspase-1 and IL-1β levels and enhanced the IL-1β secretion. These in vitro findings were validated in archival brain tissues from Simian Immunodeficiency Virus (SIV)-infected and uninfected rhesus macaques. Further validation of NLRP3 priming in vivo involved administration of lipopolysac-charide (LPS) to HIV transgenic (Tg) rats followed by assessment of IL-1β mRNA expression and inflammasome activation (ASC oligomers and mature IL-1β). Intriguingly, LPS potentiated upregulation of IL-1β mRNA and inflammasome activation in HIV-Tg rats compared with the wild-type controls. Interestingly, we found an inverse relationship in the expression of NLRP3 and its negative regulator, miR-223, suggesting a miR-223-mediated mechanism for Tat-induced NLRP3 priming. Furthermore, blockade of NLRP3 resulted in decreased IL-1β secretion. Collectively, these findings suggest a novel role of Tat in priming and activating the NLRP3 inflammasome. Therefore, NLRP3 can be envisioned as a therapeutic target for ameliorating Tat-mediated neuroinflammation.

Original languageEnglish (US)
Pages (from-to)3599-3609
Number of pages11
JournalJournal of Neuroscience
Volume37
Issue number13
DOIs
StatePublished - Mar 29 2017

Keywords

  • HIV-1 Tat
  • Inflammasome
  • Microglia
  • NLRP3
  • Neuroinflammation

ASJC Scopus subject areas

  • Neuroscience(all)

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