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Published on: November 22, 2024
Regulation of MMPs and TIMPs by IL-1beta during corneal ulceration and infection
Mei Lang Xue1, Denis Wakefield, Mark D P Willcox
1Cooperative Research Centre for Eye Research and Technology and Cornea and Contact Lens Research Unit, School of Optometry and Vision Science, The University of New South Wales, Sydney, New South Wales, Australia.
Purpose:
This study was conducted to investigate the role of IL-1beta in the regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in a mouse model of experimental keratitis and corneal injury.
Methods:
Mice were injected subconjunctivally with 10 micro g of anti-mouse IL-1beta antibody 2 hours before challenge with Pseudomonas aeruginosa (strain 6294). Control animals received an equal volume and concentration of isotype control antibody at the same time. Eyes were enucleated at 0, 8, 24, and 72 hours, after bacterial challenge and processed for histologic examination. Some eyes were homogenized and used to evaluate production of MMP-2, MMP-9, TIMP-1, and TIMP-2 protein, by zymography and reverse zymography.
Results:
Injury without bacterial infection resulted in increases in both MMP-2 and -9 and a slight but significant downregulation of TIMP-1. Administration of anti-IL-1beta just before injury and without bacterial infection resulted in a significant reduction in expression of MMP-2 (at 8 hours), MMP-9 (at 8 hours), TIMP-1 (at 8 and 72 hours), and TIMP-2 (at 8 hours). Mice treated with anti-IL-1beta antibody, before bacterial challenge, demonstrated markedly reduced corneal damage compared with the severe corneal injury and massive neutrophil infiltration observed in infected mice treated with control antibody. Administration of the neutralizing anti-IL-1beta antibody resulted in a significant reduction of MMP-9 and a change in the time course of TIMP-1 and -2 expression. The reduction in MMP-9 by anti-IL-1beta during infection was much greater than the reduction without infection.
Conclusions:
The results imply that IL-1beta has a central role in corneal destruction during bacterial keratitis and suggests that targeting IL-1beta may be a novel therapeutic strategy for microbial keratitis.
Insights
Interleukin-1 beta (IL-1beta) drives corneal destruction in bacterial keratitis by increasing matrix metalloproteinases (MMPs). Neutralizing IL-1beta significantly reduces corneal damage and MMP levels, suggesting it as a therapeutic target.
Area of Science:
- Ophthalmology
- Immunology
- Microbiology
Background:
- Bacterial keratitis can lead to severe corneal damage and vision loss.
- Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play a critical role in tissue remodeling and degradation.
- Interleukin-1 beta (IL-1beta) is a key inflammatory cytokine implicated in various ocular diseases.
Purpose of the Study:
- To investigate the role of IL-1beta in regulating MMPs and TIMPs during experimental bacterial keratitis.
- To evaluate the therapeutic potential of targeting IL-1beta in a mouse model of corneal injury and infection.
Main Methods:
- Mice with experimental keratitis induced by Pseudomonas aeruginosa were treated with anti-IL-1beta antibody or isotype control.
- Corneal damage, neutrophil infiltration, and expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 were assessed.
- Zymography and reverse zymography were used to quantify protein levels.
Main Results:
- IL-1beta neutralization significantly reduced corneal damage and neutrophil infiltration.
- Anti-IL-1beta treatment markedly decreased MMP-9 levels during infection.
- Expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 was altered by IL-1beta blockade.
Conclusions:
- IL-1beta plays a central role in mediating corneal destruction in bacterial keratitis.
- Targeting IL-1beta represents a promising therapeutic strategy for microbial keratitis.
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