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From the Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan.
PURPOSE. To determine the role of Toll-like receptor 4 (TLR4) in Pseudomonas aeruginosa (P. aeruginosa) keratitis in resistant (cornea-healing) BALB/c mice.
METHODS. Corneal TLR4 mRNA levels were tested by real-time PCR in BALB/c mice before and after infection. Clinical score, slit lamp, histopathology, bacterial counts, and polymorphonuclear neutrophil (PMN) quantitation were performed in the infected cornea of TLR4-deficient (TLR4lps-d) and wild-type BALB/c mice. mRNA for IL-1ß, MIP-2, IFN-
, IL-18, inducible nitric oxide synthase (iNOS), and ß-defensin-2 levels were measured by real-time PCR. Protein levels for IL-1ß, MIP-2, and IFN- were tested by ELISA.
RESULTS. In resistant BALB/c mice, TLR4 mRNA expression was significantly upregulated in the cornea after P. aeruginosa infection. In contrast, TLR4-deficient mice were susceptible to infection with P. aeruginosa and showed increased corneal opacity, PMN infiltration, bacterial counts, and perforated infected corneas. After infection, TLR4-deficient mice also showed increased mRNA expression of proinflammatory cytokines (IL-1ß and MIP-2) and type-1–associated cytokines (IFN- and IL-18) when compared with wild-type BALB/c mice. ELISA analyses showed that IL-1ß, MIP-2, and IFN- protein levels also were significantly upregulated in the cornea of TLR4-deficient versus wild-type mice. In contrast, levels of iNOs and ß-defensin-2 were significantly decreased in TLR4-deficient compared with wild-type mice.
CONCLUSIONS. TLR4 is critical in host resistance to P. aeruginosa, as its deficiency results in increased PMN infiltration and proinflammatory cytokine production, decreased iNOs and ß-defensin-2 production, impaired bacterial killing, and a susceptible phenotype.
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