Matrix Metalloproteinases and Tumor Necrosis Factor α in Glaucomatous Optic Nerve Head

Abstract

To study expression and location of matrix metalloproteinases (MMPs) and tumor necrosis factor ␣ (TNF-␣) in glaucomatous optic nerve heads, which are known to be secreted in response to a variety of neuronal injury.Methods: Four postmortem eyes from patients with primary open-angle glaucoma, 7 eyes from patients with normal-pressure glaucoma, and 4 eyes from age-matched normal donors were studied by immunohistochemistry. The sections of the optic nerve heads were examined after immunostaining with antibodies to MMPs (MMP-1, MMP-2, and MMP-3), TNF-␣, or TNF-␣ receptor 1. Results:The intensity of the immunostaining and the number of stained cells for MMPs, TNF-␣, or TNF-␣ receptor 1 were greater in the glaucomatous optic nerve heads, particularly in eyes with normal-pressure glaucoma compared with age-matched controls. Positive immunostaining was observed in all regions of the glauco-matous optic nerve heads, but most prominently in the postlaminar region. Immunostaining was observed mainly in glial cells and their processes around the axons and blood vessels and in pial septae. Conclusion:There is increased immunostaining for MMPs, TNF-␣ and TNF-␣ receptor 1 in the glaucomatous optic nerve head, which suggests increased expression of these proteins in glaucoma and thereby implies a role in the tissue remodeling and degenerative changes seen in glaucomatous optic nerve heads.Clinical Relevance: The MMPs and TNF-␣ may be components of astroglial activation that occurs in glaucomatous optic nerve heads. The biological alterations in the expression of these proteins may play a role in the progression of glaucomatous optic neuropathy.

TNF-α signaling in glaucomatous neurodegeneration

“…This up-regulation exhibited a close association with the cumulative IOP exposure and neuronal damage (available at www.iovs.org, 2005; 46:EAbstract 3772). Similar to glaucomatous human eyes Yan et al, 2000), increased TNF-α immunolabeling in ocular hypertensive rat eyes compared with the controls was mainly localized to glial cells. However, retinal TNF-R1 immunolabeling in the ocular hypertensive eyes was most prominent on RGCs and their axons.…”

“…Parallel studies through immunohistochemical analysis of human donor eyes revealed an increased immunolabeling for TNF-α and TNF-R1 in the optic nerve head (Yan et al, 2000) and retina ) of glaucomatous eyes compared to age-matched controls. Using in situ hybridization, mRNA signals for TNF-α or TNF-R1 were also found to be similarly more intense in glaucomatous eyes relative to controls .…”

“…Glial production of TNF-α is increased in the retina and optic nerve head, and TNF-R1 is up-regulated in RGCs and their axons in glaucomatous human donor eyes Yan et al, 2000;Yuan and Neufeld, 2000). Findings of ongoing in vivo studies support that TNF-α and TNF-R1 are also up-regulated following experimental elevation of intraocular pressure (IOP), and TNF-α signaling is involved in the RGC death process during neurodegeneration in ocular hypertensive eyes.…”

“…TNF-α also activates matrix metalloproteinases (Gottschall and Yu, 1995), which are not only involved in tissue remodeling in the glaucomatous optic nerve head (Yan et al, 2000), but have also be associated with neurotoxicity. Retinal matrix metalloproteinase activity has been related to RGC death including that induced by IOP elevation (Guo et al, 2005).…”

“…However, another study utilizing TNF-α knockout mice has shown a significantly higher number of preserved axons within the degenerating distal nerve stump (Siebert and Bruck, 2003), thereby suggesting that despite the debris removal function of invading macrophages, TNF-α secreted by these cells may also mediate axonal damage. It is highly warranted to determine the pathogenic importance of TNF-α signaling for axon degeneration in glaucoma, since in addition to increased TNF-α production of neighboring cells, optic nerve axons prominently express TNF-R1, which is up-regulated in glaucoma Yan et al, 2000;Yuan and Neufeld, 2000).…”