Regulation of Pseudomonas aeruginosa corneal infection in IL-1 beta converting enzyme (ICE, caspase-1) deficient mice

PURPOSE: Antibody neutralization studies have shown that in Pseudomonas aeruginosa corneal infection, IL-1 beta is critical to regulation of the host inflammatory response, but mechanisms remain undetermined. To elucidate these mechanisms, caspase-1 knockout (ICE(-/-)) mice, that do not release mature IL-1 beta after endotoxin challenge, were tested. METHODS: Clinical scores, MPO activity (for PMN quantitation), bacterial plate count, semiquantitative RT-PCR, ELISA and TUNEL staining were used to characterize the inflammatory response after infection in knockout and C57BL/6 (B6) wild type mice. RESULTS: Clinical scores were significantly reduced in ICE(-/-) vs. B6 mice at 3, 5 and 7 days postinfection (p.i.). The decreased inflammatory response of ICE(-/-) mice was striking at 1 day p.i., and bacterial load also was significantly reduced in the cornea of the knockout mice at 3-7 days p.i. Knockout mice exhibited significantly increased mRNA and protein levels for IL-1Ra, the physiological regulator of IL-1 activity, and in addition, a significant increase in the number of apoptotic cells were quantitated in the corneal epithelium of ICE(-/-) vs. B6 mice at 1 day p.i. CONCLUSIONS: These data provide evidence that bacterial infection in the cornea of ICE(-/-) mice induces a reduced inflammatory response by: reduction in PMN and cytokines and chemokines that attract these cells to the cornea; enhanced apoptotic cell death in the infected epithelium; and increased IL-1Ra levels. The data also confirm the importance of IL-1 regulation in this model and suggest that ICE inhibition may be an attractive ancillary therapeutic strategy to control the host response to this pathogen.