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TLR4 Is Required for Host Resistance in Pseudomonas aeruginosa Keratitis

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 (TLR4^lps-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.

This article has been cited by other articles:

				L. C. Huang, R. Y. Reins, R. L. Gallo, and A. M. McDermott Cathelicidin-Deficient (Cnlp / ) Mice Show Increased Susceptibility to Pseudomonas aeruginosa Keratitis Invest. Ophthalmol. Vis. Sci., October 1, 2007; 48(10): 4498 - 4508. [Abstract] [Full Text] [PDF]

				X. Huang, W. Du, R. P. Barrett, and L. D. Hazlett ST2 Is Essential for Th2 Responsiveness and Resistance to Pseudomonas aeruginosa Keratitis Invest. Ophthalmol. Vis. Sci., October 1, 2007; 48(10): 4626 - 4633. [Abstract] [Full Text] [PDF]