Activation of protease-activated receptors in astrocytes evokes a novel neuroprotective pathway through release of chemokines of the growth-regulated oncogene/cytokine-induced neutrophil chemoattractant family

Yingfei Wang, Weibo Luo, Georg Reiser

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Activation of protease-activated receptors (PARs) is known to exert neuroprotection when low concentrations of the agonist protease thrombin are applied. However, the mechanism of protection is still unclear. Here, we showed that activation of multiple PARs, including PAR-1, PAR-2 and PAR-4, was able to elevate the release of the chemokine cytokine-induced neutrophil chemoattractant (CINC)-3 from rat astrocytes, in addition to evoking CINC-1 secretion. Different molecular mechanisms were identified as being involved in the secretion of CINC-1 and CINC-3, upon activation of different PARs. Importantly, we found that both CINC-1 and CINC-3 could signal to rat cortical neurons. Both chemokines acted via CXCR2 to prevent C2-ceramide-induced cytochrome c release from mitochondria. Consequently CINC-1 and CINC-3 protected neurons from apoptosis. We further revealed that conditioned media obtained from PAR-activated astrocytes similarly protected cortical neurons against C 2-ceramide-induced cell death. The neuroprotection was considerably suppressed by a CXCR2 antagonist. CXCR2 is the cognate receptor for CINC. Therefore, our findings demonstrate that PAR-activated astrocytes are able to protect neurons against neurodegeneration and cell death via regulation of the secretion of chemokines CINC-1 and CINC-3. These data indicate a previously unknown mechanism for astrocyte-mediated neuroprotection achieved by PAR activation.

Original languageEnglish (US)
Pages (from-to)3159-3168
Number of pages10
JournalEuropean Journal of Neuroscience
Volume26
Issue number11
DOIs
StatePublished - Dec 1 2007

Fingerprint

Proteinase-Activated Receptors
Chemotactic Factors
Oncogenes
Chemokines
Astrocytes
Neutrophils
Cytokines
Growth
Neurons
Cell Death
PAR-2 Receptor
PAR-1 Receptor
Cytokine Receptors
Ceramides
Conditioned Culture Medium
Cytochromes c
Thrombin
Mitochondria
Peptide Hydrolases

Keywords

  • Cytokine-induced neutrophil chemoattractant
  • Growth-regulated oncogene
  • Neuroprotection
  • Rat astrocytes
  • Signal transduction
  • Thrombin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

@article{f9e3c1d8071346e2a2634772a7ceb4ac,
title = "Activation of protease-activated receptors in astrocytes evokes a novel neuroprotective pathway through release of chemokines of the growth-regulated oncogene/cytokine-induced neutrophil chemoattractant family",
abstract = "Activation of protease-activated receptors (PARs) is known to exert neuroprotection when low concentrations of the agonist protease thrombin are applied. However, the mechanism of protection is still unclear. Here, we showed that activation of multiple PARs, including PAR-1, PAR-2 and PAR-4, was able to elevate the release of the chemokine cytokine-induced neutrophil chemoattractant (CINC)-3 from rat astrocytes, in addition to evoking CINC-1 secretion. Different molecular mechanisms were identified as being involved in the secretion of CINC-1 and CINC-3, upon activation of different PARs. Importantly, we found that both CINC-1 and CINC-3 could signal to rat cortical neurons. Both chemokines acted via CXCR2 to prevent C2-ceramide-induced cytochrome c release from mitochondria. Consequently CINC-1 and CINC-3 protected neurons from apoptosis. We further revealed that conditioned media obtained from PAR-activated astrocytes similarly protected cortical neurons against C 2-ceramide-induced cell death. The neuroprotection was considerably suppressed by a CXCR2 antagonist. CXCR2 is the cognate receptor for CINC. Therefore, our findings demonstrate that PAR-activated astrocytes are able to protect neurons against neurodegeneration and cell death via regulation of the secretion of chemokines CINC-1 and CINC-3. These data indicate a previously unknown mechanism for astrocyte-mediated neuroprotection achieved by PAR activation.",
keywords = "Cytokine-induced neutrophil chemoattractant, Growth-regulated oncogene, Neuroprotection, Rat astrocytes, Signal transduction, Thrombin",
author = "Yingfei Wang and Weibo Luo and Georg Reiser",
year = "2007",
month = "12",
day = "1",
doi = "10.1111/j.1460-9568.2007.05938.x",
language = "English (US)",
volume = "26",
pages = "3159--3168",
journal = "European Journal of Neuroscience",
issn = "0953-816X",
publisher = "Wiley-Blackwell",
number = "11",

}

TY - JOUR

T1 - Activation of protease-activated receptors in astrocytes evokes a novel neuroprotective pathway through release of chemokines of the growth-regulated oncogene/cytokine-induced neutrophil chemoattractant family

AU - Wang, Yingfei

AU - Luo, Weibo

AU - Reiser, Georg

PY - 2007/12/1

Y1 - 2007/12/1

N2 - Activation of protease-activated receptors (PARs) is known to exert neuroprotection when low concentrations of the agonist protease thrombin are applied. However, the mechanism of protection is still unclear. Here, we showed that activation of multiple PARs, including PAR-1, PAR-2 and PAR-4, was able to elevate the release of the chemokine cytokine-induced neutrophil chemoattractant (CINC)-3 from rat astrocytes, in addition to evoking CINC-1 secretion. Different molecular mechanisms were identified as being involved in the secretion of CINC-1 and CINC-3, upon activation of different PARs. Importantly, we found that both CINC-1 and CINC-3 could signal to rat cortical neurons. Both chemokines acted via CXCR2 to prevent C2-ceramide-induced cytochrome c release from mitochondria. Consequently CINC-1 and CINC-3 protected neurons from apoptosis. We further revealed that conditioned media obtained from PAR-activated astrocytes similarly protected cortical neurons against C 2-ceramide-induced cell death. The neuroprotection was considerably suppressed by a CXCR2 antagonist. CXCR2 is the cognate receptor for CINC. Therefore, our findings demonstrate that PAR-activated astrocytes are able to protect neurons against neurodegeneration and cell death via regulation of the secretion of chemokines CINC-1 and CINC-3. These data indicate a previously unknown mechanism for astrocyte-mediated neuroprotection achieved by PAR activation.

AB - Activation of protease-activated receptors (PARs) is known to exert neuroprotection when low concentrations of the agonist protease thrombin are applied. However, the mechanism of protection is still unclear. Here, we showed that activation of multiple PARs, including PAR-1, PAR-2 and PAR-4, was able to elevate the release of the chemokine cytokine-induced neutrophil chemoattractant (CINC)-3 from rat astrocytes, in addition to evoking CINC-1 secretion. Different molecular mechanisms were identified as being involved in the secretion of CINC-1 and CINC-3, upon activation of different PARs. Importantly, we found that both CINC-1 and CINC-3 could signal to rat cortical neurons. Both chemokines acted via CXCR2 to prevent C2-ceramide-induced cytochrome c release from mitochondria. Consequently CINC-1 and CINC-3 protected neurons from apoptosis. We further revealed that conditioned media obtained from PAR-activated astrocytes similarly protected cortical neurons against C 2-ceramide-induced cell death. The neuroprotection was considerably suppressed by a CXCR2 antagonist. CXCR2 is the cognate receptor for CINC. Therefore, our findings demonstrate that PAR-activated astrocytes are able to protect neurons against neurodegeneration and cell death via regulation of the secretion of chemokines CINC-1 and CINC-3. These data indicate a previously unknown mechanism for astrocyte-mediated neuroprotection achieved by PAR activation.

KW - Cytokine-induced neutrophil chemoattractant

KW - Growth-regulated oncogene

KW - Neuroprotection

KW - Rat astrocytes

KW - Signal transduction

KW - Thrombin

UR - http://www.scopus.com/inward/record.url?scp=36248946610&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36248946610&partnerID=8YFLogxK

U2 - 10.1111/j.1460-9568.2007.05938.x

DO - 10.1111/j.1460-9568.2007.05938.x

M3 - Article

C2 - 18005059

AN - SCOPUS:36248946610

VL - 26

SP - 3159

EP - 3168

JO - European Journal of Neuroscience

JF - European Journal of Neuroscience

SN - 0953-816X

IS - 11

ER -