Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection

Farsbid Noorbakhsh, Nathalie Vergnolle, Justin C. McArthur, Claudia Silva, Mohammed Vodjgani, Patricia Andrade-Gordon, Morley D. Hollenberg, Christopher Power

Research output: Contribution to journalArticlepeer-review

Abstract

Proteinase-activated receptors (PARs), a newly discovered subgroup of G-protein coupled receptors, are widely expressed by neural cells, but their roles in the nervous system remain uncertain. In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia. The inflammatory cytokines TNF-α and IL-1β were also increased in HIV-1-associated dementia brains compared with patients without dementia (p < 0.05), but these same cytokines induced PAR-2 expression on neurons. Enhanced PAR-2 expression and subsequent activation prevented neuronal cell death and induction of the tumor suppressor, p53, caused by the HIV-encoded protein, Tat (p < 0.01). Intrastriatal implantation of a PAR-2 peptide agonist also inhibited Tat-induced neurotoxkity in a mouse model of HIV neuropathogenesis (p < 0.05). Moreover, PAR-2 null animals showed more severe neuroinflammation and neuronal loss caused by Tat neurotoxicity (p < 0.05). TNF-α protected wild-type neurons from Tat-related neurotoxicity, but in PAR-2-deficient neurons, the same concentrations of TNF-α were cytotoxic (p < 0.001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death.

Original languageEnglish (US)
Pages (from-to)7320-7329
Number of pages10
JournalJournal of Immunology
Volume174
Issue number11
DOIs
StatePublished - Jun 1 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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