Traumatic brain injury induced matrix metalloproteinase2 cleaves CXCL12α (stromal cell derived factor 1α) and causes neurodegeneration.
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.
Laboratory of CNS Injury and Repair, Neuroscience Institute, JFK Medical Center, 65 James St, Edison, NJ 08820, United States; Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States. Electronic address: pmamuneer@gmail.com.
P M Abdul
PMA
Muneer
Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States.
Adriano Andrea
AA
Conte
Laboratory of CNS Injury and Repair, Neuroscience Institute, JFK Medical Center, 65 James St, Edison, NJ 08820, United States; Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States.
Debanjan
D
Haldar
Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States.
Mathew
M
Long
Laboratory of CNS Injury and Repair, Neuroscience Institute, JFK Medical Center, 65 James St, Edison, NJ 08820, United States; Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States.
Rachel K
RK
Patel
Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ 07103, United States.
Vijayalakshmi
V
Santhakumar
Departments of Biochemistry and Molecular Biology, and Oral Biological and Medical Sciences, University of British Columbia, 2199 Westbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
Christopher M
CM
Overall
Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States. Electronic address: pfister@njit.edu.
Bryan J
BJ
Pfister
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000070642:Brain Injuries, Traumatic / Q000201:enzymology* / Q000235:genetics; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D000074624:NADPH Oxidase 1 / Q000096:biosynthesis / Q000235:genetics; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics*; D009474:Neurons / Q000187:drug effects; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12; D061965:Matrix Metalloproteinase Inhibitors; D034741:RNA, Small Interfering; D000074624:NADPH Oxidase 1; C000614712:NOX1 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2
Apoptosis; CXCL12; MMP2; Neurodegeneration; Oxidative stress; Stromal cell derived factor; Traumatic brain injury