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MMP9 cleavage of the ?4 integrin ectodomain leads to recurrent epithelial erosions in mice.

ABSTRACT: Integrin ?6?4 is an integral membrane protein within hemidesmosomes and it mediates adhesion of epithelial cells to their underlying basement membrane. During wound healing, disassembly of hemidesmosomes must occur for sheet movement-mediated cell migration. The mechanisms of disassembly and reassembly of hemidesmosomes are not fully understood. The current study was initiated to understand the underlying cause of recurrent corneal erosions in the mouse. Here, we show that in vivo: (1) MMP9 levels are elevated and ?4 integrin is partially cleaved in epithelial cell extracts derived from debridement wounded corneas; (2) the ?4 ectodomain is missing from sites where erosions develop; and (3) ?4 cleavage can be reduced by inhibiting MMP activity. Although ?4, ?3 and ?1 integrins were all cleaved by several MMPs, only MMP9 was elevated in cell extracts derived from corneas with erosions. Coimmunoprecipitation studies showed that ?4 integrin associates with MMP9, and protein clustering during immunoprecipitation induced proteolytic cleavage of the ?4 integrin extracellular domain, generating a 100 kDa ?4 integrin cytoplasmic domain fragment. Confocal imaging with three-dimensional reconstruction showed that MMP9 localizes at erosion sites in vivo where the ectodomain of ?4 integrin is reduced or absent. MMP activation experiments using cultured corneal and epidermal keratinocytes showed reduced levels of ?6?4 and ?1 integrins within 20 minutes of phorbol ester treatment. This report is the first to show that ?4 integrin associates with MMP9 and that its ectodomain is a target for cleavage by MMP9 in vivo under pathological conditions.

SUBMITTER: Pal-Ghosh S

PROVIDER: S-EPMC3138707 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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MMP9 cleavage of the β4 integrin ectodomain leads to recurrent epithelial erosions in mice.

Pal-Ghosh Sonali S Blanco Tomas T Tadvalkar Gauri G Pajoohesh-Ganji Ahdeah A Parthasarathy Arpitha A Zieske James D JD Stepp Mary Ann MA

Journal of cell science 20110712 Pt 15

Integrin α6β4 is an integral membrane protein within hemidesmosomes and it mediates adhesion of epithelial cells to their underlying basement membrane. During wound healing, disassembly of hemidesmosomes must occur for sheet movement-mediated cell migration. The mechanisms of disassembly and reassembly of hemidesmosomes are not fully understood. The current study was initiated to understand the underlying cause of recurrent corneal erosions in the mouse. Here, we show that in vivo: (1) MMP9 leve ...[more]

PMID: 21750188

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Project description:Purpose: To observe the therapeutic effect of low-temperature plasma ablation in treating patients with recurrent corneal erosions (RCEs). Materials and Methods: From 2020 to 2022, 35 participants with unilateral RCEs voluntarily enrolled. Here, 35 eyes of 35 patients were treated with low-temperature plasma ablation (coblation). All surgeries were performed by the same doctor (X.H.). The coblation went back and forth over the entire erosion area around five times for about five minutes. After the operation, patients were scheduled for follow-up visits at the outpatient clinic after 1 month, 3 months, 6 months, and 12 months, and at the end of the trial. During every visit, each patient underwent an evaluation of their ocular symptoms utilizing the following: pain score, intraocular pressure, slit lamp biomicroscopic examination, dry eye analysis, corneal topography, and corneal in vivo confocal microscopy (IVCM). Results: The mean follow-up time was 12.4 ± 6.1 months, ranging from 6 to 29 months. Of the 35 patients who had low-temperature plasma ablation, 32 eyes (91.43%) were completely symptom-free and three (8.57%) eyes had repeated episodes of recurrent corneal erosions after the surgery, at 3, 10, and 12 months, respectively. The typical RCE morphologic abnormalities observed in IVCM included the deformation and relaxation of the corneal epithelium, disorganized stromal fibers, reduced nerve fiber density, and disordered organization. After low-temperature plasma ablation, the loose cysts disappeared, and the epithelium became solid and tight. There was no obvious difference in the intraocular pressure (p = 0.090) or corneal astigmatism (p = 0.175) before and after treatment. The mean pain score decreased significantly, with a preoperative score of 7.7 ± 2.4 and postoperative score of 1.1 ± 1.8 (p < 0.001). The mean corneal thickness decreased from 562.6 ± 42.2 mm to 549.6 ± 26.9 mm (p = 0.031). The mean non-invasive keratograph tear meniscus height (NIKTMH) decreased from 0.210 ± 0.054 mm to 0.208 ± 0.045 mm (p = 0.001), and the mean TBUT decreased from 6.191 ± 2.811 s to 5.815 ± 2.802 s (p < 0.001), which manifested as a slight worsening of dry eyes. In one case, the patient’s corneal astigmatism became more severe, which may be related to the high instantaneous energy when the operation did not flush in a timely manner, and it was recovered after 6 months. Conclusions: Low-temperature plasma ablation is an effective and safe procedure to treat patients with recurrent corneal erosions.

Dataset Information

MMP9 cleavage of the ?4 integrin ectodomain leads to recurrent epithelial erosions in mice.

Publications

MMP9 cleavage of the β4 integrin ectodomain leads to recurrent epithelial erosions in mice.

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