The interleukin-1 receptor (IL-1R) plays an important role in mediating the inflammatory responses against pathogens. However, it is not clear whether a sustained IL-1R signaling following the loss of its endogenous inhibitor, IL-1R antagonist (IL-1RA), could improve mucosal immunity against the murine enteropathogen, Citrobacter rodentium. At basal levels, IL-1RA-deficient (IL1raKO) mice displayed an elevated inflammatory tone as indicated by their higher levels of circulating neutrophils, and the inflammatory marker, lipocalin-2, in both systemic and luminal contents. We reasoned that the heightened inflammatory tone of IL1raKO mice may be beneficial in clearing C. rodentium efficiently, but such was not the case. Oral challenge of C. rodentium (1 × 109 colony-forming units/mouse) resulted in luminal colonization, which peaked at day 7 postinfection, in both wild-type and IL1raKO mice. However, IL1raKO mice displayed a higher C. rodentium burden, and exacerbated colonic inflammation and hyperplasia. The aggravated infection in IL1raKO mice was corroborated using in vivo imaging of mice infected with a bioluminescent strain of C. rodentium. However, IL1raKO mice do not display any defect in their neutrophils with respect to their recruitment to the inflamed gut, generation of neutrophil extracellular traps and reactive oxygen species, or their ability to kill C. rodentium in vitro. In contrast, the macrophages of IL1raKO mice were able to upregulate more inducible nitric oxide synthase and produce more nitrite that wild-type macrophages; however, the former was less effective in mediating killing of C. rodentium in vitro. Together, our results suggest that IL-1RA plays a protective role in combating enteropathogen infection.
Yeoh et al. (Mon,) studied this question.