title: CCR7 deficiency causes diarrhea associated with altered ion transport in colonocytes in the absence of overt colitis.
abstract: The chemokine receptor CCR7 is a central regulator in the maintenance of cellular homeostasis of mucosal tissues. CCR7⁻/⁻ mice develop autoimmune gastritis and exocrinopathy accompanied by the formation of mucosal tertiary lymphoid follicles. Here we found that CCR7-deficient mice frequently suffered from chronic diarrhea linked with increased gastrointestinal motility and the development of severe anorectal prolapse. Enhanced formation of intestinal lymphoid follicles was associated with an elevated proportion of activated colonic T cells and increased production of the cytokine interleukin (IL)-1β. To uncover the pathomechanisms of diarrhea in CCR7⁻/⁻ mice, colonic epithelial barrier and ion channel activities were analyzed in Ussing chambers. Although overt acute colitis was absent, CCR7 deficiency resulted in reduced electrogenic sodium absorption and colonic chloride secretion. As it is known that IL-1β regulates epithelial sodium channel (ENaC) activity, these data imply a causal link between CCR7 expression, IL-1β level, and Na⁺ malabsorption owing to altered ENaC expression and diarrhea.
authors.affiliation: Medical Clinic I, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schumann
authors.forename: S
authors.initials: S
authors.lastname: Winter
authors.forename: K
authors.initials: K
authors.lastname: Wichner
authors.forename: C
authors.initials: C
authors.lastname: May
authors.forename: A A
authors.initials: AA
authors.lastname: Kühl
authors.forename: A
authors.initials: A
authors.lastname: Batra
authors.forename: B
authors.initials: B
authors.lastname: Siegmund
authors.forename: M
authors.initials: M
authors.lastname: Zeitz
authors.forename: J-D
authors.initials: JD
authors.lastname: Schulzke
authors.forename: M
authors.initials: M
authors.lastname: Lipp
authors.forename: U E
authors.initials: UE
authors.lastname: Höpken
mesh_terms: D000818:Animals; D015415:Biomarkers; D002712:Chlorides / Q000378:metabolism; D003092:Colitis / Q000235:genetics* / Q000378:metabolism*; D003106:Colon / Q000276:immunology / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D003967:Diarrhea / Q000235:genetics* / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis; D007413:Intestinal Mucosa; D017136:Ion Transport; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054400:Receptors, CCR7 / Q000172:deficiency* / Q000235:genetics; D012005:Rectal Prolapse / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002712:Chlorides; D053503:Epithelial Sodium Channels; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D053583:Interleukin-1beta; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019005:Cystic Fibrosis Transmembrane Conductance Regulator