Research Article

Decreased TNF Levels and Improved Retinal Ganglion Cell Survival in MMP-2 Null Mice Suggest a Role for MMP-2 as TNF Sheddase

Figure 5

Mechanisms of TNF-induced neurodegeneration in the glaucomatous retina. In the glaucomatous retina, bioactive, soluble TNF is released by the Müller glia. Upon binding to its receptor TNF-R1 on the RGCs, TNF induces apoptosis, via activation of the caspase (caspase-8) signaling cascade, loss of mitochondrial membrane potential, and generation of reactive oxygen species. On the other hand, TNF is also involved in a complex interplay between proinflammatory, proapoptosis, and prosurvival pathways, which indirectly affect RGC survival, via nitric oxide production, modulation of neuronal excitability and excitotoxicity, expression and release of MMPs (including MMP-9), synthesis and secretion of vasoactive endothelin-1, amyloid-beta neurotoxicity, BRB disruption, and neurotoxicity of secreted cytokines and recruited microglia and T-cells. Notably, in this paper, we propose a novel in vivo function for MMP-2, as an activating sheddase of TNF. Drawings by Ramon Y. Cajal.