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Matrix metalloproteinase activity stimulates N-cadherin shedding and the soluble N-cadherin ectodomain promotes
Katherine Conant1, Stefano Daniele2, P Lorenzo Bozzelli2
1Department of Neuroscience, Georgetown University School of Medicine, Washington, D.C., USA. kec84@georgetown.edu.
Background:
Matrix metalloproteinases (MMPs) are a family of enzymes that are typically released from intracellular stores to act on specific extracellular substrates. MMP expression and activity can be increased in a neuronal activity-dependent manner, and further increased in response to tissue injury. MMP substrates include cell adhesion molecules (CAMs) that are abundantly expressed in the brain and well positioned for membrane proximal cleavage. Importantly, CAM integrity is important to synaptic structure and axon-myelin interactions, and shed ectodomains may themselves influence cellular function.
Methods:
In the present study, we have examined proteolysis of N-cadherin (N-cdh) by MMP-7, a family member that has been implicated in disorders including HIV dementia, multiple sclerosis, and major depression. With in vitro digest assays, we tested N-cdh cleavage by increasing concentrations of recombinant enzyme. We also tested MMP-7 for its potential to stimulate N-cdh shedding from cultured neural cells. Since select CAM ectodomains may interact with cell surface receptors that are expressed on microglial cells, we subsequently tested the N-cdh ectodomain for its ability to stimulate activation of this cell type as determined by nuclear translocation of NF-κB, Iba-1 expression, and TNF-α release.
Results:
We observed that soluble N-cdh increased Iba-1 levels in microglial lysates, and also increased microglial release of the cytokine TNF-α. Effects were associated with increased NF-κB immunoreactivity in microglial nuclei and diminished by an inhibitor of the toll-like receptor adaptor protein, MyD88.
Conclusions:
Together, these in vitro results suggest that soluble N-cdh may represent a novel effector of microglial activation, and that disorders with increased MMP levels may stimulate a cycle in which the products of excess proteolysis further exacerbate microglial-mediated tissue injury. Additional in vivo studies are warranted to address this issue.
Insights
Matrix metalloproteinase-7 (MMP-7) cleaves N-cadherin, releasing soluble fragments that activate microglia. This suggests a mechanism where excess MMP activity exacerbates neuroinflammation and tissue damage in neurological disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Matrix metalloproteinases (MMPs) are enzymes involved in extracellular matrix remodeling.
- MMP activity increases with neuronal activity and tissue injury, cleaving cell adhesion molecules (CAMs).
- CAM integrity is crucial for synaptic structure and axon-myelin interactions; shed ectodomains can influence cellular function.
Purpose of the Study:
- To investigate the proteolysis of N-cadherin (N-cdh) by MMP-7.
- To determine if MMP-7 stimulates N-cdh shedding from cultured neural cells.
- To assess the effect of soluble N-cadherin ectodomain on microglial activation.
Main Methods:
- In vitro digest assays using recombinant MMP-7 and N-cadherin.
- Cultured neural cells were treated with MMP-7 to assess N-cadherin shedding.
- Microglial activation was measured by NF-κB translocation, Iba-1 expression, and TNF-α release after exposure to N-cadherin ectodomain.
Main Results:
- Soluble N-cadherin increased Iba-1 levels and TNF-α release in microglial cells.
- These effects were linked to increased NF-κB immunoreactivity in microglial nuclei.
- The microglial activation was partially inhibited by blocking the MyD88 pathway.
Conclusions:
- Soluble N-cadherin acts as a novel effector of microglial activation.
- Increased MMP levels in neurological disorders may initiate a cycle of microglial-mediated tissue injury.
- Further in vivo studies are needed to confirm these findings.
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