title: NHE3 modulates the severity of colitis in IL-10-deficient mice.
abstract: NHE3, the major intestinal Na(+)/H(+) exchanger, was shown to be downregulated and/or inhibited in patients with inflammatory bowel disease (IBD), a phenomenon believed to contribute to inflammation-associated diarrhea. NHE3(-/-) mice spontaneously develop colitis and demonstrate high susceptibility to dextran sulfate-induced mucosal injury. We investigated the effects of NHE3 deficiency on the development of chronic colitis in an IL-10 knockout (KO) mouse model of Crohn's disease. NHE3(-/-) mice were first backcrossed to 129/SvEv mice for >10 generations, with no apparent changes in their survival or phenotype. These mice were crossed with IL-10(-/-) mice on the same genetic background, and the phenotypes of 10-wk-old wild-type (WT), IL-10(-/-), NHE3(-/-), and IL-10(-/-)/NHE3(-/-) (double-KO) mice were studied. Histological and immunohistochemical examination of the colon established important architectural alterations, including increased neutrophilic and mononuclear cell infiltration in double- compared with single-KO mice. Double-KO mice demonstrated increased colonic expression of neutrophil collagenase matrix metalloproteinase-8 and the chemokines macrophage inflammatory protein-2, CXCL1, CXCL10, and CXCL11. Colonic IFNγ, IL-17, and IL-12/23 p40 protein secretion was significantly increased in double- compared with single-KO mice. IL-10(-/-)/NHE3(-/-) mouse colonic epithelium exhibited increased hallmarks of apoptosis, including a significantly increased number of cleaved caspase-3-positive surface epithelial cells. These results highlight the importance of NHE3 in the maintenance of intestinal barrier integrity and in modulating the inflammatory process in IL-10-deficient mice. Chronic NHE3 inhibition or underexpression observed in IBD may therefore contribute to the pathogenesis of IBD by influencing the extent of the epithelial barrier defect and affect the ultimate degree of inflammation.
authors.affiliation: Department of Pediatrics, Steele Children’s Research Center, University of Arizona Health Sciences Center, Tucson, 85724, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Larmonier
authors.forename: D
authors.initials: D
authors.lastname: Laubitz
authors.forename: R D
authors.initials: RD
authors.lastname: Thurston
authors.forename: A L
authors.initials: AL
authors.lastname: Bucknam
authors.forename: F M
authors.initials: FM
authors.lastname: Hill
authors.forename: M
authors.initials: M
authors.lastname: Midura-Kiela
authors.forename: R
authors.initials: R
authors.lastname: Ramalingam
authors.forename: P R
authors.initials: PR
authors.lastname: Kiela
authors.forename: F K
authors.initials: FK
authors.lastname: Ghishan
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005838:Genotype; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D012720:Severity of Illness Index; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*
chemical_list: D019743:Chemokines, CXC; C556062:IL10 protein, mouse; D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D016753:Interleukin-10; D007371:Interferon-gamma; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020784:Matrix Metalloproteinase 8