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

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

SUBMITTER: Boucher AA

PROVIDER: S-EPMC7026906 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Boucher Alexander A AA Rosenfeldt Leah L Mureb Duaa D Shafer Jessica J Sharma Bal Krishan BK Lane Adam A Crowther Rebecca R RR McKell Melanie C MC Whitt Jordan J Alenghat Theresa T Qualls Joseph J Antoniak Silvio S Mackman Nigel N Flick Matthew J MJ Steinbrecher Kris A KA Palumbo Joseph S JS

Journal of thrombosis and haemostasis : JTH 20191011 1

<h4>Background</h4>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.<h4>Objective</h4>Determine the specific contributions of PAR-1 expressed by macrophages and colonic enterocytes to infectious colitis.<h4>Methods</h4>Mice carrying a conditional PAR-1 allele were generated and bred to m ...[more]

PMID: 31539206

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Project description:The causes of gastrointestinal complaints in irritable bowel syndrome (IBS) remain poorly understood. Altered nerve function has emerged as an important pathogenic factor as IBS mucosal biopsy supernatants consistently activate enteric and sensory neurons. We investigated the neurally active molecular components of such supernatants from patients with IBS and quiescent ulcerative colitis (UC).Effects of supernatants from 7 healthy controls (HC), 20 IBS and 12 UC patients on human and guinea pig submucous neurons were studied with neuroimaging techniques. We identify differentially expressed proteins with proteome analysis.Nerve activation by IBS supernatants was prevented by the protease activated receptor 1 (PAR1) antagonist SCHE79797. UC supernatants also activated enteric neurons through protease dependent mechanisms but without PAR1 involvement. Proteome analysis of the supernatants identified 204 proteins, among them 17 proteases as differentially expressed between IBS, UC and HC. Of those the four proteases elastase 3a, chymotrypsin C, proteasome subunit type beta-2 and an unspecified isoform of complement C3 were significantly more abundant in IBS compared to HC and UC supernatants. Of eight proteases, which were upregulated in IBS, the combination of elastase 3a, cathepsin L and proteasome alpha subunit-4 showed the highest prediction accuracy of 98% to discriminate between IBS and HC groups. Elastase synergistically potentiated the effects of histamine and serotonin-the two other main neuroactive substances in the IBS supernatants. A serine protease inhibitor isolated from the probiotic Bifidobacterium longum NCC2705 (SERPINBL), known to inhibit elastase-like proteases, prevented nerve activation by IBS supernatants.Proteases in IBS and UC supernatants were responsible for nerve activation. Our data demonstrate that proteases, particularly those signalling through neuronal PAR1, are biomarker candidates for IBS, and protease profiling may be used to characterise IBS.

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

Publications

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

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