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MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment
Inge Van Hove1,2, Evy Lefevere3,4, Lies De Groef5,6
1Neural Circuit Development and Regeneration Research Group, Department of Biology, Katholieke Universiteit Leuven (KU Leuven), B-3000 Leuven, Belgium. inge.vanhove@kuleuven.be.
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.
Insights
Matrix metalloproteinase-3 (MMP-3) plays a key role in ocular inflammation by promoting leukocyte infiltration in the eye. Reducing MMP-3 levels can significantly decrease inflammatory responses in conditions like endotoxin-induced uveitis (EIU).
Area of Science:
- Ophthalmology
- Immunology
- Neuroscience
Background:
- Matrix metalloproteinase-3 (MMP-3) is implicated in neuroinflammation and central nervous system barrier disruption.
- The posterior eye, including the retina and retinal pigment epithelium (RPE), is affected by neuroinflammation, but MMP-3's role in ocular inflammation is unclear.
Purpose of the Study:
- To investigate the contribution of MMP-3 to acute ocular inflammation using the endotoxin-induced uveitis (EIU) model.
- To determine if MMP-3 deficiency impacts key inflammatory markers and cellular infiltration in the eye during EIU.
Main Methods:
- Induced acute ocular inflammation in mice using systemic lipopolysaccharide administration.
- Assessed MMP-3 mRNA and protein expression in the posterior eye.
- Utilized MMP-3 deficient mice and knockdown strategies to evaluate the impact on leukocyte adhesion, infiltration, and inflammatory gene expression.
Main Results:
- Lipopolysaccharide administration increased MMP-3 expression in the posterior eye.
- MMP-3 deficiency or knockdown significantly reduced retinal leukocyte adhesion and vitreous cavity infiltration in EIU mice.
- Loss of MMP-3 decreased the expression of key inflammatory molecules (ICAM-1, IL-6, iNOS, TNF-α) and chemokines (MCP-1, CXCL1) in the retina and RPE.
Conclusions:
- MMP-3 significantly contributes to acute ocular inflammation in the EIU model.
- MMP-3 inhibition or deficiency effectively suppresses inflammatory cell infiltration and mediator upregulation in the eye.
- MMP-3 represents a potential therapeutic target for managing ocular inflammatory diseases.
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