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

• Published in: Journal of thrombosis and haemostasis Vol. 18; no. 1; pp. 91 - 103
• Main Authors: Boucher, Alexander A., Rosenfeldt, Leah, Mureb, Duaa, Shafer, Jessica, Sharma, Bal Krishan, Lane, Adam, Crowther, Rebecca R., McKell, Melanie C., Whitt, Jordan, Alenghat, Theresa, Qualls, Joseph, Antoniak, Silvio, Mackman, Nigel, Flick, Matthew J., Steinbrecher, Kris A., Palumbo, Joseph S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01-01-2020
• Subjects: Abscesses; Animals; CD3 antigen; CD4 antigen; Citrobacter; Citrobacter rodentium; Clonal deletion; Colitis; Colitis - genetics; Colitis - microbiology; Cre recombinase; Enterobacteriaceae Infections; Enterocytes; Helper cells; Hypertrophy; Inflammatory bowel disease; Lymphocytes T; Macrophages; Mice; Mice, Inbred C57BL; myeloid cells; PAR‐1; Pathogenesis; Proteinase; Receptor, PAR-1 - genetics; Th17 Cells; PAR-1; colitis; myeloid cells; Citrobacter rodentium; enterocytes
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.14641

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.