Abstract
Matrix metalloproteinases (MMPs) are involved in the pathology of numerous inflammatory retinal degenerations, including retinitis pigmentosa (RP). Our previous work revealed that intravitreal injections with tissue inhibitor of metalloproteinases 1 (TIMP-1) reduce the progression of rod cell death and inhibit cone cell remodeling that involves reactive gliosis in retinal Müller glial cells (MGCs) in rodent models. The underlying cellular and molecular mechanisms of how TIMP-1 functions in the retina remain to be resolved; however, MGCs are involved in structural homeostasis, neuronal cell survival and death. In the present study, MMP-9 and TIMP-1 expression patterns were investigated in a human MGC line (MIO-M1) under inflammatory cytokine (IL-1β and TNF-α) and oxidative stress (H2O2) conditions. First, both IL-1β and TNF-α, but not H2O2, have a mild in vitro pro-survival effect on MIO-M1 cells. Treatment with either cytokine results in the imbalanced secretion of MMP-9 and TIMP-1. H2O2 treatment has little effect on their secretion. The investigation of their intracellular expression led to interesting observations. MMP-9 and TIMP-1 are both expressed, not only in the cytoplasm, but also inside the nucleus. None of the treatments alters the MMP-9 intracellular distribution pattern. In contrast to MMP-9, TIMP-1 is detected as speckles. Intracellular TIMP-1 aggregation forms in the cytoplasmic area with IL-1β treatment. With H2O2 treatments, the cell morphology changes from cobbles to spindle shapes and the nuclei become larger with increases in TIMP-1 speckles in an H2O2 dose-dependent manner. Two TIMP-1 cell surface receptors, low density lipoprotein receptor-related protein-1 (LRP-1) and cluster of differentiation 82 (CD82), are expressed within the nucleus of MIO-M1 cells. Overall, these observations suggest that intracellular TIMP-1 is a target of proinflammatory and oxidative insults in the MGCs. Given the importance of the roles for MGCs in the retina, the functional implication of nuclear TIMP-1 and MMP-9 in MGCs is discussed.
Highlights
Inherited forms of retinitis pigmentosa (RP) are initiated with rod cell death, followed by the rearrangement and degeneration of cone photoreceptor cells [1, 2]
We hypothesized that MGCs express endogenous Matrix metalloproteinases (MMPs)-9 and TIMP1, the expression of which is altered in retinal remodeling during retinal degeneration. We investigated how these proteins are expressed in human MGCs under normal, inflammatory, Nuclear Matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in retinal Muller glial cells are modulated by cytokines and oxidative stress and oxidative stress conditions
In the present study using MIO-M1 culture system, we examined if MGCs express MMP-9 and TIMP-1 in response to proinflammatory conditions such as exposure to cytokines and oxidative stress that precipitates retinal degeneration
Summary
Inherited forms of retinitis pigmentosa (RP) are initiated with rod cell death, followed by the rearrangement and degeneration of cone photoreceptor cells [1, 2]. MGCs undergo reactive gliosis, a homeostasis-maintaining process to keep the functional integrity of the retina. TIMP-1 cytokine-like activities can be exerted dependently or independently of the interaction with MMP-9 [11]. It still remains unknown how the expression and interaction of MMP-9 and TIMP-1 are regulated and affect the functions of MGCs in the retina. MMP-9 is rarely detected in healthy retina [13]; the upregulation of MMP-9 expression is associated with the retinal degeneration in rodent RP models [14,15,16]
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