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L. C. Huang, R. Y. Reins, R. L. Gallo, A. M. McDermott; Cathelicidin-Deficient (cnlp-/-) Mice Show Increased Susceptibility to Pseudomonas Aeruginosa Keratitis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4725.
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The ocular surface epithelia express the antimicrobial peptide cathelicidin. We have previously shown that cathelicidin exerts potent activity against Pseudomonas aeruginosa (PA) and modulates cytokine production in corneal epithelial cells in vitro. Here we examined the clinical progression and innate immune responses during PA keratitis in cathelicidin-deficient (KO) mice.
PA (ATCC 19660) keratitis was induced in six to eight-week old KO mice and wild-type (WT) littermates generated on the 129/SVJ background. Clinical score and histopathology were utilized to monitor the progression of infection at 1, 3, 7, 14 and 21 days post infection (p.i.). Mouse corneas were harvested for viable bacteria quantitation, and myeloperoxidase (MPO) assays were performed to determine the number of infiltrating neutrophils. ELISA was used to quantitate interleukin (IL)-1ß, IL-6, macrophage inflammatory peptide (MIP)-2, keratinocyte-derived chemokine (KC), tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF) levels in the corneas.
WT mice were resistant (cornea healed) whilst KO mice showed increased susceptibility (cornea failed to recover by 21 days or perforated) to PA infection. Clinical scores were significantly elevated in the infected corneas of KO mice vs. WT mice at 7, 14, and 21 days post-infection (n=12 per time point). Absence of cathelicidin resulted in significantly delayed clearance of PA in the cornea and increased number of infiltrating neutrophils at 1, 3, 7, and 14 days p.i. (n=10 per time point). KO mice also exhibited differential expression of protein levels for IL-1ß, IL-6, MIP-2, KC, TNF-α and VEGF up to day 21 p.i. compared to the WT mice (n=10).
Cathelicidin-deficient mice showed considerably more susceptibility to PA keratitis compared to the wild type mice. Our data demonstrate direct in vivo evidence that endogenous expression of cathelicidin provides defense against corneal PA infection indicating its importance in host innate immunity at the ocular surface.
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