title: Deficiency in Duox2 activity alleviates ileitis in GPx1- and GPx2-knockout mice without affecting apoptosis incidence in the crypt epithelium.
abstract: Mice deficient in glutathione peroxidase (GPx)-1 and -2 (GPx1-/-GPx2-/-double knockout or DKO mice) develop very-early-onset (VEO) ileocolitis, suggesting that lack of defense against reactive oxygen species (ROS) renders susceptibility to intestinal inflammation. Two members of ROS-generating NADPH oxidase family, NOX1 and DUOX2, are highly inducible in the intestinal epithelium. Previously, we reported that Nox1 deficiency ameliorated the pathology in DKO mice (Nox1-TKO). The role of Duox2 in ileocolitis of the DKO mice is evaluated here in Duoxa-TKO mice by breeding DKO mice with Duoxa-/-mice (Duoxa-TKO), which do not have Duox2 activity. Similar to Nox1-TKO mice, Duoxa-TKO mice no longer have growth retardation, shortened intestine, exfoliation of crypt epithelium, crypt abscesses and depletion of goblet cells manifested in DKO mice by 35 days of age. Unlike Nox1-TKO mice, Duoxa-TKO mice still have rampant crypt apoptosis, elevated proliferation, partial loss of Paneth cells and diminished crypt density. Treating DKO mice with NOX inhibitors (di-2-thienyliodonium/DTI and thioridazine/THZ) and an antioxidant (mitoquinone/MitoQ) significantly reduced gut pathology. Furthermore, in the inflamed human colon, DUOX protein expression is highly elevated in the apical, lateral and perinuclear membrane along the whole length of gland. Taken together, we conclude that exfoliation of crypt epithelium, but not crypt apoptosis, is a major contributor to inflammation. Both Nox1 and Duox2 induce exfoliation of crypt epithelium, but only Nox1 induces apoptosis. NOX1 and DUOX2 may be potential therapeutic targets for treating ileocolitis in human patients suffering inflammatory bowel disease (IBD).
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, China; Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, 1450 E Duarte Road, Duarte, CA 91010, USA. Electronic address: fchu@coh.org.
authors.forename: Fong-Fong
authors.initials: FF
authors.lastname: Chu
authors.affiliation: Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: R Steven
authors.initials: RS
authors.lastname: Esworthy
authors.affiliation: Center for Cancer Research and Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Helmut
authors.initials: H
authors.lastname: Grasberger
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Donko
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Leto
authors.affiliation: Department of Gastroenterology and Hepatology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Binghui
authors.initials: B
authors.lastname: Shen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003106:Colon / Q000378:metabolism / Q000473:pathology; D000074623:Dual Oxidases / Q000235:genetics*; D005979:Glutathione Peroxidase / Q000235:genetics; D006801:Humans; D007079:Ileitis / Q000235:genetics* / Q000473:pathology; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000074624:NADPH Oxidase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D009861:Onium Compounds; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013876:Thiophenes; D000094765:Glutathione Peroxidase GPX1
chemical_list: D009861:Onium Compounds; D017382:Reactive Oxygen Species; D013876:Thiophenes; C051503:iodonium thiophene; D000074623:Dual Oxidases; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; C000614831:Duox2 protein, mouse; D000094765:Glutathione Peroxidase GPX1
keywords: Double-knockout mouse; Dual oxidase-2; Glutathione peroxidase; NADPH oxidase; Very-early-onset inflammatory-bowel-disease