Norepinephrine as the Intrinsic Contributor to Contact Lens-Induced Pseudomonas aeruginosa Keratitis

by Selleckchem | Sep 11 2023

Purpose: Contact lens wear (CLW) is one of the leading risk factors for Pseudomonas aeruginosa keratitis (PAK). However, the intrinsic factors that contribute to the high susceptibility to keratitis during CLW remain to be elucidated. CLW over an extended period can elevate corneal norepinephrine (NE) concentration. In this study, we investigated the role of NE in promoting PAK.

Methods: We constructed an injury-induced PAK model and a CLW-induced PAK model to confirm the impact of NE during corneal infection. Pharmacological blockage of NE and gene knockdown mouse were used to investigate the downstream effector of NE. RNA sequencing was performed to explore the cellular alterations during NE treatment. Non-parametric Mann-Whitney U test or Kruskal-Wallis test were used to ascertain the significance (P < 0.05).

Results: Supplementation of NE led to PAK even without artificial corneal injury during CLW. The effect was mediated by the β2-adrenergic receptor (β2-AR) in the corneal epithelium. The β2-AR blockage by the NE antagonist ICI118,551 (ICI) or by deleting of its encoding gene Adrb2 significantly alleviated infection during CLW. Conversely, β2-AR activation compromised the integrity of the epithelium and significantly increased the cortical plaque marker ezrin. Transcriptome analysis identified that the protective effect of ICI on the keratitis was mediated by dual-specificity phosphatases. Suramin, a Dusp5 antagonist, abrogated the protective effect of ICI.

Conclusions: These data reveal a new mechanism by which NE acts as an intrinsic factor that promotes CLW-induced PAK and provide novel therapeutic targets for treating keratitis by targeting NE-β2-AR.

Comments:

The purpose of the study described is to investigate the role of norepinephrine (NE) in promoting Pseudomonas aeruginosa keratitis (PAK), specifically in the context of contact lens wear (CLW). PAK is a type of corneal infection, and CLW is known to be a significant risk factor for developing this condition. The study aimed to elucidate the intrinsic factors that contribute to the increased susceptibility to PAK during CLW.

The researchers employed two models to examine the impact of NE during corneal infection: an injury-induced PAK model and a CLW-induced PAK model. They used pharmacological methods to block NE and performed gene knockdown in mice to investigate the downstream effectors of NE. Additionally, they conducted RNA sequencing to analyze cellular alterations caused by NE treatment. Statistical analysis, such as the non-parametric Mann-Whitney U test or Kruskal-Wallis test, was employed to determine the significance of the findings.

The results of the study demonstrated that the supplementation of NE promoted PAK even without artificial corneal injury during CLW. The effect was mediated by the β2-adrenergic receptor (β2-AR) present in the corneal epithelium. Blocking β2-AR using the NE antagonist ICI118,551 (ICI) or deleting its encoding gene Adrb2 significantly alleviated the infection during CLW. Conversely, activation of β2-AR compromised the integrity of the epithelium and increased the expression of the cortical plaque marker ezrin. Through transcriptome analysis, the researchers identified that the protective effect of ICI on keratitis was mediated by dual-specificity phosphatases. Furthermore, they found that suramin, an antagonist of Dusp5 (a dual-specificity phosphatase), abolished the protective effect of ICI.

In conclusion, the study uncovered a new mechanism by which NE acts as an intrinsic factor that promotes PAK during CLW. It identified the NE-β2-AR pathway as a potential therapeutic target for treating keratitis associated with contact lens wear. By targeting this pathway, novel interventions could be developed to mitigate the risk of PAK in individuals wearing contact lenses.