Abstract
Matrix metalloproteinase-3 (MMP-3) is known to mediate neuroinflammatory processes by activating microglia, disrupting blood–central nervous system barriers and supporting neutrophil influx into the brain. In addition, the posterior part of the eye, more specifically the retina, the retinal pigment epithelium (RPE) and the blood–retinal barrier, is affected upon neuroinflammation, but a role for MMP-3 during ocular inflammation remains elusive. We investigated whether MMP-3 contributes to acute inflammation in the eye using the endotoxin-induced uveitis (EIU) model. Systemic administration of lipopolysaccharide induced an increase in MMP-3 mRNA and protein expression level in the posterior part of the eye. MMP-3 deficiency or knockdown suppressed retinal leukocyte adhesion and leukocyte infiltration into the vitreous cavity in mice subjected to EIU. Moreover, retinal and RPE mRNA levels of intercellular adhesion molecule 1 (Icam1), interleukin 6 (Il6), cytokine-inducible nitrogen oxide synthase (Nos2) and tumor necrosis factor α (Tnfα), which are key molecules involved in EIU, were clearly reduced in MMP-3 deficient mice. In addition, loss of MMP-3 repressed the upregulation of the chemokines monocyte chemoattractant protein (MCP)-1 and (C-X-C motif) ligand 1 (CXCL1). These findings suggest a contribution of MMP-3 during EIU, and its potential use as a therapeutic drug target in reducing ocular inflammation.
Highlights
The eye has evolved into a specialized, tightly regulated immune privileged organ with structural and functional mechanisms that need to protect the integrity of the neural retina and maintain retinal homeostasis
Acute systemic ocular inflammation can be induced in rodents using the endotoxin-induced uveitis (EIU) model, i.e., by intraperitoneal injection of the endotoxin lipopolysaccharide (LPS), the major component of the outer membrane of gram-negative bacteria
To evaluate whether Matrix metalloproteinase-3 (MMP-3) is important during EIU in the posterior segment of the eye, the matrix metalloproteinases (MMPs)-3 mRNA and protein levels were determined at different time points post LPS injection
Summary
The eye has evolved into a specialized, tightly regulated immune privileged organ with structural and functional mechanisms that need to protect the integrity of the neural retina and maintain retinal homeostasis. The blood–retinal barrier (BRB) performs a crucial function to maintain this ocular immune privilege Both inner and outer components of the BRB, formed by, respectively, endothelial and retinal pigment epithelial (RPE) cells, physically separate the retina from the immune system and prevent leukocyte infiltration from the blood vessels into the retina. Acute systemic ocular inflammation can be induced in rodents using the endotoxin-induced uveitis (EIU) model, i.e., by intraperitoneal injection of the endotoxin lipopolysaccharide (LPS), the major component of the outer membrane of gram-negative bacteria This model mainly mimics acute inflammatory responses, driven by innate immune mechanisms [1], and is invaluable in unraveling the ocular inflammatory mediators. We investigated the involvement of MMP-3 in endotoxin-induced acute inflammation in the posterior part of the mouse eye
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