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

Nirmal K. Phulwani, Tammy Kielian

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 1 2008

Fingerprint

Poly(ADP-ribose) Polymerases
Astrocytes
Chemical activation
Staphylococcus aureus
Innate Immunity
Protein Isoforms
Poly (ADP-Ribose) Polymerase-1
DNA Repair Enzymes
Interleukin-1beta
Neuroglia
Small Interfering RNA
Nitric Oxide
Homeostasis
Tumor Necrosis Factor-alpha
Pathogens

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Poly (ADP-ribose) polymerases (PARPs) 1-3 regulate astrocyte activation. / Phulwani, Nirmal K.; Kielian, Tammy.

In: Journal of Neurochemistry, Vol. 106, No. 2, 01.07.2008, p. 578-590.

Research output: Contribution to journalArticle

@article{f0659db0b3f34a10bc22538ee947090c,
title = "Poly (ADP-ribose) polymerases (PARPs) 1-3 regulate astrocyte activation",
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.",
keywords = "Astrocytes, Chemokines, PARP, PJ-34, Proinflammatory cytokines, Staphylococcus aureus, siRNA",
author = "Phulwani, {Nirmal K.} and Tammy Kielian",
year = "2008",
month = "7",
day = "1",
doi = "10.1111/j.1471-4159.2008.05403.x",
language = "English (US)",
volume = "106",
pages = "578--590",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Poly (ADP-ribose) polymerases (PARPs) 1-3 regulate astrocyte activation

AU - Phulwani, Nirmal K.

AU - Kielian, Tammy

PY - 2008/7/1

Y1 - 2008/7/1

N2 - 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.

AB - 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.

KW - Astrocytes

KW - Chemokines

KW - PARP

KW - PJ-34

KW - Proinflammatory cytokines

KW - Staphylococcus aureus

KW - siRNA

UR - http://www.scopus.com/inward/record.url?scp=51649101403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=51649101403&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2008.05403.x

DO - 10.1111/j.1471-4159.2008.05403.x

M3 - Article

C2 - 18410506

AN - SCOPUS:51649101403

VL - 106

SP - 578

EP - 590

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 2

ER -