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

• Published in: PloS one 2021-07, Vol.16 (7), p.e0253915-e0253915
• Main Authors: Lee, Eun-Jin, Zheng, Mengmei, Craft, Cheryl Mae, Jeong, Shinwu
• Format: Article
• Language: English
• Subjects: Animal models; Apoptosis; Biology and Life Sciences; Cell culture; Cell death; Cell morphology; Cell surface; Cell survival; Cytokines; Cytology; Cytoplasm; Gelatinase B; Glial cells; Gliosis; Homeostasis; Hydrogen peroxide; Inflammation; Intracellular; Laboratories; Low density lipoprotein; Low density lipoprotein receptors; Matrix metalloproteinase; Matrix metalloproteinases; Medicine; Medicine and Health Sciences; Metabolism; Metalloproteinase; Molecular modelling; Morphology; Mueller cells; Nuclei (cytology); Oxidative stress; Proteins; Reagents; Receptor density; Receptors; Research and Analysis Methods; Retina; Retinitis; Retinitis pigmentosa; Survival; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0253915

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 (H 2 O 2 ) conditions. First, both IL-1β and TNF-α, but not H 2 O 2, 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. H 2 O 2 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 H 2 O 2 treatments, the cell morphology changes from cobbles to spindle shapes and the nuclei become larger with increases in TIMP-1 speckles in an H 2 O 2 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.