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MMP-8 Is Critical for Dexamethasone Therapy in Alkali-Burned Corneas Under Dry Eye Conditions
Fang Bian1, Changjun Wang1, Johanna Tukler-Henriksson1
1Department of Ophthalmology, Baylor College of Medicine, Houston, Texas.
Abstract:
Our previous studies have shown that Dexamethasone (Dex) reduced the expression of matrix-metalloproteinases (MMPs -1,-3,-9,-13), IL-1β and IL-6, while it significantly increased MMP-8 mRNA transcripts in a concomitant dry eye and corneal alkali burn murine model (CM). To investigate if MMP-8 induction is responsible for some of the protective effects of Dex in CM, MMP-8 knock out mice (MMP-8KO) were subjected to the CM for 2 or 5 days and topically treated either with 2 μl of 0.1% Dexamethasone (Dex), or saline QID. A separate group of C57BL/6 mice were topically treated with Dex or BSS and received either 100 nM CAM12 (MMP-8 inhibitor) or vehicle IP, QD. Here we demonstrate that topical Dex treated MMP-8KO mice subjected to CM showed reduced corneal clarity, increased expression of inflammatory mediators (IL-6, CXCL1, and MMP-1 mRNA) and increased neutrophil infiltration at 2D and 5D compared to Dex treated WT mice. C57BL/6 mice topically treated with Dex and CAM12 IP recapitulated findings seen with MMP-8KO mice. These results suggest that some of the anti-inflammatory effects of Dex are mediated through increased MMP-8 expression. J. Cell. Physiol. 231: 2506-2516, 2016. © 2016 Wiley Periodicals, Inc.
Insights
Dexamethasone (Dex) protects the cornea by increasing matrix metalloproteinase-8 (MMP-8). MMP-8 knockout mice showed worsened inflammation and corneal clarity after injury when treated with Dex, indicating MMP-8 mediates Dex
Area of Science:
- Ophthalmology
- Immunology
- Molecular Biology
Background:
- Dexamethasone (Dex) has shown protective effects in a murine model of dry eye and corneal alkali burn (CM).
- Previous studies indicated Dex reduces certain matrix metalloproteinases (MMPs) and inflammatory cytokines but increases MMP-8 mRNA.
- The role of MMP-8 in Dex-mediated protection in CM remained unclear.
Purpose of the Study:
- To investigate if MMP-8 induction is responsible for some of the protective effects of Dexamethasone (Dex) in a corneal alkali burn and dry eye model.
- To elucidate the mechanism of Dexamethasone's anti-inflammatory action in ocular surface disease.
Main Methods:
- Mice lacking MMP-8 (MMP-8KO) and wild-type (WT) C57BL/6 mice were subjected to CM.
- Mice received topical Dexamethasone (Dex) or saline/BSS, with some C57BL/6 mice also receiving an MMP-8 inhibitor (CAM12).
- Corneal clarity, inflammatory mediator expression (IL-6, CXCL1, MMP-1), and neutrophil infiltration were assessed at 2 and 5 days post-injury.
Main Results:
- Dex-treated MMP-8KO mice exhibited reduced corneal clarity and increased inflammatory mediators (IL-6, CXCL1, MMP-1 mRNA) and neutrophil infiltration compared to Dex-treated WT mice.
- Mice treated with both Dex and an MMP-8 inhibitor (CAM12) showed similar negative outcomes as MMP-8KO mice.
- These findings highlight a critical role for MMP-8 in the anti-inflammatory response.
Conclusions:
- The anti-inflammatory and protective effects of Dexamethasone (Dex) in the corneal alkali burn and dry eye model are, in part, mediated by the induction of MMP-8.
- MMP-8 plays a significant role in mitigating corneal inflammation and preserving corneal clarity following injury.
- Targeting MMP-8 could be a potential therapeutic strategy for ocular surface inflammatory conditions.
