| First Author | Boucher AA | Year | 2020 |
| Journal | J Thromb Haemost | Volume | 18 |
| Issue | 1 | Pages | 91-103 |
| PubMed ID | 31539206 | Mgi Jnum | J:287178 |
| Mgi Id | MGI:6391609 | Doi | 10.1111/jth.14641 |
| Citation | Boucher AA, et al. (2020) Cell type-specific mechanisms coupling protease-activated receptor-1 to infectious colitis pathogenesis. J Thromb Haemost 18(1):91-103 |
| abstractText | 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(DeltaM) ) or enterocyte-specific (PAR-1(DeltaEPI) ) 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-1beta, IL-22, IL-6, and IL-17A. In contrast, infected PAR-1(DeltaM) mice lost less weight and had fewer crypt abscesses relative to controls. PAR-1(DeltaM) 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(DeltaM) mice exhibited lower levels of IL-1beta, but not Th17-related cytokines (ie, IL-22, IL-6, IL-17A). Infected PAR-1(DeltaEPI) 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. |
