title: Aquaporin-3 mediates hydrogen peroxide-dependent responses to environmental stress in colonic epithelia.
abstract: The colonic epithelium provides an essential barrier against the environment that is critical for protecting the body and controlling inflammation. In response to injury or gut microbes, colonic epithelial cells produce extracellular hydrogen peroxide (H2O2), which acts as a potent signaling molecule affecting barrier function and host defense. In humans, impaired regulation of H2O2in the intestine has been associated with early-onset inflammatory bowel disease and colon cancer. Here, we show that signal transduction by H2O2depends on entry into the cell by transit through aquaporin-3 (AQP3), a plasma membrane H2O2-conducting channel. In response to injury, AQP3-depleted colonic epithelial cells showed defective lamellipodia, focal adhesions, and repair after wounding, along with impaired H2O2responses after exposure to the intestinal pathogen Citrobacter rodentium Correspondingly, AQP3-/-mice showed impaired healing of superficial wounds in the colon and impaired mucosal innate immune responses against C. rodentium infection, manifested by reduced crypt hyperplasia, reduced epithelial expression of IL-6 and TNF-α, and impaired bacterial clearance. These results elucidate the signaling mechanism of extracellular H2O2in the colonic epithelium and implicate AQP3 in innate immunity at mucosal surfaces.
authors.affiliation: Department of Gastroenterology, Nutrition, and Hepatology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115; jay.thiagarajah@childrens.harvard.edu.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Thiagarajah
authors.affiliation: Department of Gastroenterology, Nutrition, and Hepatology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Gastroenterology, Nutrition, and Hepatology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Jeremy A
authors.identifier: 0000-0002-0749-2357
authors.initials: JA
authors.lastname: Goettel
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143.|Department of Physiology, University of California, San Francisco, CA 94143.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
authors.affiliation: Department of Gastroenterology, Nutrition, and Hepatology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Wayne I
authors.initials: WI
authors.lastname: Lencer
mesh_terms: D000818:Animals; D051400:Aquaporin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D044082:Citrobacter rodentium / Q000276:immunology / Q000472:pathogenicity; D003106:Colon / Q000276:immunology / Q000293:injuries / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007413:Intestinal Mucosa / Q000276:immunology / Q000293:injuries / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D013312:Stress, Physiological; D014945:Wound Healing / Q000502:physiology
chemical_list: C496027:AQP3 protein, human; C496028:Aqp3 protein, mouse; D051400:Aquaporin 3; D006861:Hydrogen Peroxide
keywords: aquaporin-3; colon; epithelium; hydrogen peroxide; microbe