Traumatic brain injury induced matrix metalloproteinase2 cleaves CXCL12α (stromal cell derived factor 1α) and causes neurodegeneration

P. M. Abdul-Muneer, Adriano Andrea Conte, Debanjan Haldar, Mathew Long, Rachel K. Patel, Vijayalakshmi Santhakumar, Christopher M. Overall, Bryan J. Pfister

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Traumatic brain injury (TBI), even at mild levels, can activate matrix metalloproteinases (MMPs) and the induction of neuroinflammation that can result in blood brain barrier breakdown and neurodegeneration. MMP2 has a significant role in neuroinflammation and neurodegeneration by modulating the chemokine CXCL12α (stromal cell derived factor SDF-1α) signaling pathway and the induction of apoptosis. SDF-1α is responsible for cell proliferation and differentiation throughout the nervous system and is also implicated in various neurodegenerative illnesses. We hypothesized that TBI leads to MMP2 activation and cleavage of the N-terminal 4 amino acid residues of CXCL12α with generation of the highly neurotoxic fragment SDF-1(5–67). Using an in vitro stretch-injury model of rat neuronal cultures and the in vivo fluid percussion injury (FPI) model in rats, we found that oxidative stress has a significant role in the activation of MMP2. This is initiated by the induction of free radical generating enzyme NADPH oxidase 1 (NOX1). Induction of NOX1 correlated well with the signatures of oxidative stress marker, 4HNE in the injured neuronal cultures and cerebral cortex of rats. Further, using MMP2 siRNA and pharmacological MMP2 inhibitor, ARP100, we established the neurodegenerative role of MMP2 in cleaving SDF-1α to a neurotoxic fragment SDF-1(5–67). By immunofluorescence, western blotting and TUNEL experiments, we show the cleaved form of SDF leads to apoptotic cell death in neurons. This work identifies a new potential therapeutic target to reduce the complications of brain damage in TBI.

Original languageEnglish (US)
Pages (from-to)190-199
Number of pages10
JournalBrain, Behavior, and Immunity
Volume59
DOIs
StatePublished - Jan 1 2017

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Chemokine CXCL12
Oxidative Stress
Percussion
In Situ Nick-End Labeling
Wounds and Injuries
Blood-Brain Barrier
Matrix Metalloproteinases
Cerebral Cortex
Nervous System
Small Interfering RNA
Free Radicals
Fluorescent Antibody Technique
Cell Differentiation
Cell Death
Western Blotting
Cell Proliferation
Pharmacology
Apoptosis
Neurons
Amino Acids

All Science Journal Classification (ASJC) codes

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

Keywords

  • Apoptosis
  • CXCL12
  • MMP2
  • Neurodegeneration
  • Oxidative stress
  • Stromal cell derived factor
  • Traumatic brain injury

Cite this

Abdul-Muneer, P. M. ; Conte, Adriano Andrea ; Haldar, Debanjan ; Long, Mathew ; Patel, Rachel K. ; Santhakumar, Vijayalakshmi ; Overall, Christopher M. ; Pfister, Bryan J. / Traumatic brain injury induced matrix metalloproteinase2 cleaves CXCL12α (stromal cell derived factor 1α) and causes neurodegeneration. In: Brain, Behavior, and Immunity. 2017 ; Vol. 59. pp. 190-199.
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abstract = "Traumatic brain injury (TBI), even at mild levels, can activate matrix metalloproteinases (MMPs) and the induction of neuroinflammation that can result in blood brain barrier breakdown and neurodegeneration. MMP2 has a significant role in neuroinflammation and neurodegeneration by modulating the chemokine CXCL12α (stromal cell derived factor SDF-1α) signaling pathway and the induction of apoptosis. SDF-1α is responsible for cell proliferation and differentiation throughout the nervous system and is also implicated in various neurodegenerative illnesses. We hypothesized that TBI leads to MMP2 activation and cleavage of the N-terminal 4 amino acid residues of CXCL12α with generation of the highly neurotoxic fragment SDF-1(5–67). Using an in vitro stretch-injury model of rat neuronal cultures and the in vivo fluid percussion injury (FPI) model in rats, we found that oxidative stress has a significant role in the activation of MMP2. This is initiated by the induction of free radical generating enzyme NADPH oxidase 1 (NOX1). Induction of NOX1 correlated well with the signatures of oxidative stress marker, 4HNE in the injured neuronal cultures and cerebral cortex of rats. Further, using MMP2 siRNA and pharmacological MMP2 inhibitor, ARP100, we established the neurodegenerative role of MMP2 in cleaving SDF-1α to a neurotoxic fragment SDF-1(5–67). By immunofluorescence, western blotting and TUNEL experiments, we show the cleaved form of SDF leads to apoptotic cell death in neurons. This work identifies a new potential therapeutic target to reduce the complications of brain damage in TBI.",
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Traumatic brain injury induced matrix metalloproteinase2 cleaves CXCL12α (stromal cell derived factor 1α) and causes neurodegeneration. / Abdul-Muneer, P. M.; Conte, Adriano Andrea; Haldar, Debanjan; Long, Mathew; Patel, Rachel K.; Santhakumar, Vijayalakshmi; Overall, Christopher M.; Pfister, Bryan J.

In: Brain, Behavior, and Immunity, Vol. 59, 01.01.2017, p. 190-199.

Research output: Contribution to journalArticle

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T1 - Traumatic brain injury induced matrix metalloproteinase2 cleaves CXCL12α (stromal cell derived factor 1α) and causes neurodegeneration

AU - Abdul-Muneer, P. M.

AU - Conte, Adriano Andrea

AU - Haldar, Debanjan

AU - Long, Mathew

AU - Patel, Rachel K.

AU - Santhakumar, Vijayalakshmi

AU - Overall, Christopher M.

AU - Pfister, Bryan J.

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Y1 - 2017/1/1

N2 - Traumatic brain injury (TBI), even at mild levels, can activate matrix metalloproteinases (MMPs) and the induction of neuroinflammation that can result in blood brain barrier breakdown and neurodegeneration. MMP2 has a significant role in neuroinflammation and neurodegeneration by modulating the chemokine CXCL12α (stromal cell derived factor SDF-1α) signaling pathway and the induction of apoptosis. SDF-1α is responsible for cell proliferation and differentiation throughout the nervous system and is also implicated in various neurodegenerative illnesses. We hypothesized that TBI leads to MMP2 activation and cleavage of the N-terminal 4 amino acid residues of CXCL12α with generation of the highly neurotoxic fragment SDF-1(5–67). Using an in vitro stretch-injury model of rat neuronal cultures and the in vivo fluid percussion injury (FPI) model in rats, we found that oxidative stress has a significant role in the activation of MMP2. This is initiated by the induction of free radical generating enzyme NADPH oxidase 1 (NOX1). Induction of NOX1 correlated well with the signatures of oxidative stress marker, 4HNE in the injured neuronal cultures and cerebral cortex of rats. Further, using MMP2 siRNA and pharmacological MMP2 inhibitor, ARP100, we established the neurodegenerative role of MMP2 in cleaving SDF-1α to a neurotoxic fragment SDF-1(5–67). By immunofluorescence, western blotting and TUNEL experiments, we show the cleaved form of SDF leads to apoptotic cell death in neurons. This work identifies a new potential therapeutic target to reduce the complications of brain damage in TBI.

AB - Traumatic brain injury (TBI), even at mild levels, can activate matrix metalloproteinases (MMPs) and the induction of neuroinflammation that can result in blood brain barrier breakdown and neurodegeneration. MMP2 has a significant role in neuroinflammation and neurodegeneration by modulating the chemokine CXCL12α (stromal cell derived factor SDF-1α) signaling pathway and the induction of apoptosis. SDF-1α is responsible for cell proliferation and differentiation throughout the nervous system and is also implicated in various neurodegenerative illnesses. We hypothesized that TBI leads to MMP2 activation and cleavage of the N-terminal 4 amino acid residues of CXCL12α with generation of the highly neurotoxic fragment SDF-1(5–67). Using an in vitro stretch-injury model of rat neuronal cultures and the in vivo fluid percussion injury (FPI) model in rats, we found that oxidative stress has a significant role in the activation of MMP2. This is initiated by the induction of free radical generating enzyme NADPH oxidase 1 (NOX1). Induction of NOX1 correlated well with the signatures of oxidative stress marker, 4HNE in the injured neuronal cultures and cerebral cortex of rats. Further, using MMP2 siRNA and pharmacological MMP2 inhibitor, ARP100, we established the neurodegenerative role of MMP2 in cleaving SDF-1α to a neurotoxic fragment SDF-1(5–67). By immunofluorescence, western blotting and TUNEL experiments, we show the cleaved form of SDF leads to apoptotic cell death in neurons. This work identifies a new potential therapeutic target to reduce the complications of brain damage in TBI.

KW - Apoptosis

KW - CXCL12

KW - MMP2

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KW - Stromal cell derived factor

KW - Traumatic brain injury

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