Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) are localized in the nucleus of retinal Müller glial cells and modulated by cytokines and oxidative stress.
Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) are localized in the nucleus of retinal Müller glial cells and modulated by cytokines and oxidative stress.
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DOI：
10.1371/journal.pone.0253915
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Jeong S
中科院分区：
文献类型：
--
作者：
Lee EJ;Zheng M;Craft CM;Jeong S
基质金属蛋白酶（MMPs）参与了许多炎症性视网膜变性的病理过程，包括色素性视网膜炎（RP）。我们之前的研究表明，在啮齿类动物模型中，玻璃体内注射组织金属蛋白酶抑制剂1 （TIMP-1）可以减少视杆细胞死亡的进展，并抑制视锥细胞重塑，其中包括视网膜<s:1>神经胶质细胞（MGCs）的反应性胶质细胞形成。TIMP-1如何在视网膜中发挥作用的潜在细胞和分子机制仍有待解决；然而，MGCs参与结构稳态、神经元细胞存活和死亡。在本研究中，研究了MMP-9和TIMP-1在炎症细胞因子（IL-1β和TNF-α）和氧化应激（H2O2）条件下在人MGC细胞系（MIO-M1）中的表达模式。首先，IL-1β和TNF-α，而不是H2O2，对MIO-M1细胞有轻微的体外促生存作用。任何一种细胞因子都会导致MMP-9和TIMP-1分泌失衡。H2O2处理对其分泌影响不大。对它们在细胞内表达的研究产生了有趣的观察结果。MMP-9和TIMP-1不仅在细胞质中表达，也在细胞核内表达。这些处理均未改变MMP-9在细胞内的分布模式。与MMP-9相反，TIMP-1被检测为斑点。在IL-1β作用下，细胞内TIMP-1聚集在细胞质区域形成。在H2O2处理下，细胞形态由鹅卵石变为纺锤形，细胞核随着TIMP-1斑点的增加而变大，并呈H2O2剂量依赖性。两种TIMP-1细胞表面受体低密度脂蛋白受体相关蛋白-1 （LRP-1）和分化簇82 （CD82）在MIO-M1细胞的细胞核内表达。总之，这些观察结果表明，细胞内TIMP-1是mgc中促炎和氧化损伤的靶标。鉴于mgc在视网膜中的重要作用，我们讨论了核TIMP-1和MMP-9在mgc中的功能意义。
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.
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