Cell Type-Specific Mechanisms Coupling Protease-Activated Receptor-1 To Infectious Colitis Pathogenesis

Background Protease-activated receptor-1 (PAR-1) plays a major role in multiple disease processes, including colitis. Understanding the mechanisms coupling PAR-1 to disease pathogenesis is complicated by the fact that PAR-1 is broadly expressed across multiple cell types. Objective Determine the specific contributions of PAR-1 expressed by macrophages and colonic enterocytes to infectious colitis. Methods Mice carrying a conditional PAR-1 allele were generated and bred to mice expressing Cre recombinase in a myeloid- (PAR-1(Delta M)) or enterocyte-specific (PAR-1(Delta EPI)) fashion. Citrobacter rodentium colitis pathogenesis was analyzed in mice with global PAR-1 deletion (PAR-1(-/-)) and cell type-specific deletions. Results Constitutive deletion of PAR-1 had no significant impact on weight loss, crypt hypertrophy, crypt abscess formation, or leukocyte infiltration in Citrobacter colitis. However, colonic shortening was significantly blunted in infected PAR-1(-/-) mice, and these animals exhibited decreased local levels of IL-1 beta, IL-22, IL-6, and IL-17A. In contrast, infected PAR-1(Delta M) mice lost less weight and had fewer crypt abscesses relative to controls. PAR-1(Delta M) mice had diminished CD3+ T cell infiltration into colonic tissue, but macrophage and CD4+ T cell infiltration were similar to controls. Also contrasting results in global knockouts, PAR-1(Delta M) mice exhibited lower levels of IL-1 beta, but not Th17-related cytokines (ie, IL-22, IL-6, IL-17A). Infected PAR-1(Delta EPI) mice exhibited increased crypt hypertrophy and crypt abscess formation, but local cytokine elaboration was similar to controls. Conclusions These studies reveal complex, cell type-specific roles for PAR-1 in modulating the immune response to Citrobacter colitis that are not readily apparent in analyses limited to mice with global PAR-1 deficiency.