Differential Roles for IL-1α and IL-1β in Pseudomonas aeruginosa Corneal Infection

Abstract

Pseudomonas aeruginosa is an important cause of dermal, pulmonary, and ocular disease. Our studies have focused on P. aeruginosa infections of the cornea (keratitis) as a major cause of blinding microbial infections. The infection leads to an influx of innate immune cells, with neutrophils making up to 90% of recruited cells during early stages. We previously reported that the proinflammatory cytokines IL-1α and IL-1β were elevated during infection. Compared with wild-type (WT), infected Il1b−/− mice developed more severe corneal disease that is associated with impaired bacterial killing as a result of defective neutrophil recruitment. We also reported that neutrophils are an important source of IL-1α and IL-1β, which peaked at 24 h postinfection. To examine the role of IL-1α compared with IL-1β in P. aeruginosa keratitis, we inoculated corneas of C57BL/6 (WT), Il1a−/−, Il1b−/−, and Il1a−/−Il1b−/− (double-knockout) mice with 5 × 104 ExoS-expressing P. aeruginosa. Il1b−/− and double-knockout mice have significantly higher bacterial burden that was consistent with delayed neutrophil and monocyte recruitment to the corneas. Surprisingly, Il1a−/− mice had the opposite phenotype with enhanced bacteria clearance compared with WT mice. Although there were no significant differences in neutrophil recruitment, Il1a−/− neutrophils displayed a more proinflammatory transcriptomic profile compared to WT with elevations in C1q expression that likely caused the phenotypic differences observed. To our knowledge, our findings identify a novel, non-redundant role for IL-1α in impairing bacterial clearance.