Cell type‐specific mechanisms coupling protease‐activated receptor‐1 to infectious colitis pathogenesis

• DOI: 10.1111/jth.14641
• Publication Date: 2019-09-20T13:05:36Z
• Authors: Alexander A. Boucher; Leah Rosenfeldt; Duaa Mureb; Jessica Shafer; Bal Krishan Sharma; Adam Lane; Rebecca R. Crowther; Melanie C. McKell; Jordan Whitt; Theresa Alenghat; Joseph Qualls; Silvio Antoniak; Nigel Mackman; Matthew J. Flick; Kris A. Steinbrecher; Joseph S. Palumbo
• Keywords: Mice, Inbred C57BL; Mice; 0303 health sciences; 03 medical and health sciences; Enterobacteriaceae Infections; Animals; Citrobacter rodentium; Th17 Cells; Receptor, PAR-1; Colitis; 3. Good health

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-1ΔM) or enterocyte-specific (PAR-1ΔEPI) 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-1β, IL-22, IL-6, and IL-17A. In contrast, infected PAR-1ΔM mice lost less weight and had fewer crypt abscesses relative to controls. PAR-1ΔM 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-1ΔM mice exhibited lower levels of IL-1β, but not Th17-related cytokines (ie, IL-22, IL-6, IL-17A). Infected PAR-1ΔEPI 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.