title: Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity.
abstract: CCL25-mediated activation of CCR9 is critical for mucosal lymphocyte recruitment to the intestine. In immune-mediated liver injury complicating inflammatory bowel disease, intrahepatic activation of this pathway allows mucosal lymphocytes to be recruited to the liver, driving hepatobiliary destruction in primary sclerosing cholangitis (PSC). However, in mice and healthy humans CCL25 expression is restricted to the small bowel, whereas few data exist on activation of this pathway in the inflamed colon despite the vast majority of PSC patients having ulcerative colitis. Herein, we show that colonic CCL25 expression is not only upregulated in patients with active colitis, but strongly correlates with endoscopic Mayo score and mucosal TNFα expression. Moreover, approximately 90% (CD4(+)) and 30% (CD8(+)) of tissue-infiltrating T-cells in colitis were identified as CCR9(+) effector lymphocytes, compared to <10% of T-cells being CCR9(+) in normal colon. Sorted CCR9(+) lymphocytes also demonstrated enhanced cellular adhesion to stimulated hepatic sinusoidal endothelium compared with their CCR9(-) counterparts when under flow. Collectively, these results suggest that CCR9/CCL25 interactions are not only involved in colitis pathogenesis but also correlate with colonic inflammatory burden; further supporting the existence of overlapping mucosal lymphocyte recruitment pathways between the inflamed colon and liver.
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom.
authors.forename: Palak J
authors.initials: PJ
authors.lastname: Trivedi
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; Dept. of Internal Medicine IV, University Hospital Jena, Jena, Germany; Center for Sepsis Control and Care, University Hospital Jena, Jena, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Bruns
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; Department of General and Colorectal Surgery, Queen Elizabeth Hospital, Birmingham, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ward
authors.affiliation: Dept. of Internal Medicine IV, University Hospital Jena, Jena, Germany; Center for Sepsis Control and Care, University Hospital Jena, Jena, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Mai
authors.affiliation: Dept. of Internal Medicine IV, University Hospital Jena, Jena, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Weston
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU), Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom; Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom. Electronic address: D.H.Adams@bham.ac.uk.
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D000328:Adult; D002448:Cell Adhesion; D019742:Chemokines, CC / Q000235:genetics*; D003092:Colitis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D054388:Receptors, CCR / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration
chemical_list: C119309:CC chemokine receptor 9; C108074:CCL25 protein, human; D019742:Chemokines, CC; D054388:Receptors, CCR
keywords: Immune-mediated liver disease; Inflammatory bowel disease; Lymphocyte recruitment; Mucosal immunity; Primary sclerosing cholangitis