Poly (ADP-ribose) polymerases (PARPs) 1-3 regulate astrocyte activation

Nirmal K. Phulwani, Tammy Kielian

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Besides their traditional role in maintaining CNS homeostasis, astrocytes also participate in innate immune responses. Indeed, we have previously demonstrated that astrocytes are capable of recognizing bacterial pathogens such as Staphylococcus aureus, a common etiologic agent of CNS infections, and respond with the robust production of numerous proinflammatory mediators. Suppression of Poly (ADP-ribose) polymerase-1 (PARP-1), a DNA repair enzyme, has been shown to attenuate inflammatory responses in several cell types including mixed glial cultures. However, a role for PARP-1 in regulating innate immune responses in purified astrocytes and the potential for multiple PARP family members to cooperatively regulate astrocyte activation has not yet been examined. The synthetic PARP-1 inhibitor PJ-34 attenuated the production of several proinflammatory mediators by astrocytes in response to S. aureus stimulation including nitric oxide, interleukin-1 beta, tumor necrosis factor-alpha, and CCL2. The release of all four mediators was partially reduced in PARP-1 knockout (KO) astrocytes compared to wild-type cells. The residual inflammatory mediator expression detected in PARP-1 KO astrocytes was further blocked with PJ-34, suggesting either non-specific effects of the drug or actions on alternative PARP isoforms. Reduction in PARP-2 or PARP-3 expression by siRNA knock down revealed that these iso- forms also contributed to inflammatory mediator regulation in response to S. aureus. Interestingly, the combined targeting of either PARP-1/PARP-2 or PARP-2/PARP-3 attenuated astrocyte inflammatory responses more effectively compared to knock down of either PARP alone, suggesting cooperativity between PARP isoforms. Collectively, these findings suggest that PARPs influence the extent of S. aureus-induced astrocyte activation.

Original languageEnglish (US)
Pages (from-to)578-590
Number of pages13
JournalJournal of Neurochemistry
Volume106
Issue number2
DOIs
StatePublished - Jul 2008

Keywords

  • Astrocytes
  • Chemokines
  • PARP
  • PJ-34
  • Proinflammatory cytokines
  • Staphylococcus aureus
  • siRNA

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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