Neuronal apoptosis is regulated by tissue inhibitor of metalloproteinases-3 and matrix metalloproteinase-3

Death receptors are transmembrane cell surface proteins of the tumor necrosis factor receptor superfamily that transmit apoptotic signals in the developing and adult nervous system. Metallproteinase activity at the cell surface strongly influences cellular vulnerability to extracellular death signals in a variety of cell types, yet the marriage of metalloproteinases and receptor signaling in the nervous system remains largely unexplored. Tissue inhibitor of metalloproteinases-3 (TIMP-3) and matrix metalloproteinase-3 (MMP-3) are expressed at low levels in the adult CNS, but in the post-ischemic brain their upregulation is associated with neuronal apoptosis. Here the interface of metalloproteinase activity and death receptor signaling in neurons is explored. The results presented support the hypothesis that neuronal death is influence by the convergence of TIMP-3/MMP-3 balance and death receptor signaling at the neuronal surface. Using an in vitro model of death receptor-mediated neuronal apoptosis, we found that TIMP-3 and MMP-3 are constitutively expressed by cultured cortical neurons. TIMP-3 is required for death-receptor mediated neuronal apoptosis, where as MMP-3 activity is neuroprotective. The underlying mechanisms by which TIMP-3 and MMP-3 modulate death receptor activation are investigated. MMP inhibition by TIMP-3 is necessary for death-receptor mediated neuronal apoptosis, and MMP-3 activity blunted cell surface interaction of death ligands and receptors. Preliminary data suggests that cortical neurons derived from TIMP-3 −/− mice may be protected from ischemic damage. The implication of metalloproteinase regulation of death-receptor mediated neuronal apoptosis is discussed.