TY - JOUR
T1 - Cell type-specific mechanisms coupling protease-activated receptor-1 to infectious colitis pathogenesis
AU - Boucher, Alexander A.
AU - Rosenfeldt, Leah
AU - Mureb, Duaa
AU - Shafer, Jessica
AU - Sharma, Bal Krishan
AU - Lane, Adam
AU - Crowther, Rebecca R.
AU - McKell, Melanie C.
AU - Whitt, Jordan
AU - Alenghat, Theresa
AU - Qualls, Joseph
AU - Antoniak, Silvio
AU - Mackman, Nigel
AU - Flick, Matthew J.
AU - Steinbrecher, Kris A.
AU - Palumbo, Joseph S.
N1 - Publisher Copyright:
© 2019 International Society on Thrombosis and Haemostasis
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - Citrobacter rodentium
KW - PAR-1
KW - colitis
KW - enterocytes
KW - myeloid cells
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U2 - 10.1111/jth.14641
DO - 10.1111/jth.14641
M3 - Article
C2 - 31539206
AN - SCOPUS:85074031595
SN - 1538-7933
VL - 18
SP - 91
EP - 103
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 1
ER -