Matrix metalloproteinase activity stimulates N-cadherin shedding and the soluble N-cadherin ectodomain promotes classical microglial activation

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 su...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of neuroinflammation Vol. 14; no. 1; p. 56
Main Authors:	Conant, Katherine, Daniele, Stefano, Bozzelli, P Lorenzo, Abdi, Tsion, Edwards, Amanda, Szklarczyk, Arek, Olchefske, India, Ottenheimer, David, Maguire-Zeiss, Kathleen
Format:	Journal Article
Language:	English
Published:	England BioMed Central 17-03-2017
Subjects:	ADAM10 Protein - metabolism ADAM10 Protein - pharmacology Animals Animals, Newborn Cadherins Cadherins - pharmacology Calcium-Binding Proteins - metabolism Cell activation Cell adhesion & migration Cell adhesion molecules Cell surface Cells, Cultured Dementia disorders Dose-Response Relationship, Drug Enzyme-Linked Immunosorbent Assay Enzymes Fibroblasts Growth factors Immunoglobulins Immunoreactivity Inflammation Ischemia Lysates Matrilysin Matrix metalloproteinase Matrix Metalloproteinases - metabolism Mental depression Metalloproteinase Mice Mice, Inbred C57BL Microfilament Proteins - metabolism Microglia - drug effects Microglia - metabolism Microglial cells Multiple sclerosis MyD88 protein Myelin Myeloid Differentiation Factor 88 - metabolism N-Cadherin Nervous system NF-kappa B - metabolism Nuclear transport Oligopeptides - pharmacology Peptides Permeability Physiology Platelet Aggregation Inhibitors - pharmacology Protein Transport - drug effects Proteins Proteolysis Rats Signal Transduction - drug effects Studies Toll-like receptors Traumatic brain injury Tumor necrosis factor Tumor necrosis factor-TNF MMP Tumor necrosis factor Matrix metalloproteinase TLR MyD88 TNF Toll-like receptor Microglia
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. 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. 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. 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.
ISSN:	1742-2094 1742-2094
DOI:	10.1186/s12974-017-0827-4