title: Hypoxic macrophages impair autophagy in epithelial cells through Wnt1: relevance in IBD.
abstract: A defective induction of epithelial autophagy may have a role in the pathogenesis of inflammatory bowel diseases. This process is regulated mainly by extracellular factors such as nutrients and growth factors and is highly induced by diverse situations of stress. We hypothesized that epithelial autophagy is regulated by the immune response that in turn is modulated by local hypoxia and inflammatory signals present in the inflamed mucosa. Our results reveal that HIF-1α and Wnt1 were co-localized with CD68 in cells of the mucosa of IBD patients. We have observed increased protein levels of β-catenin, phosphorylated mTOR, and p62 and decreased expression of LC3II in colonic epithelial crypts from damaged mucosa in which β-catenin positively correlated with phosphorylated mTOR and negatively correlated with autophagic protein markers. In cultured macrophages, HIF-1 mediated the increase in Wnt1 expression induced by hypoxia, which enhanced protein levels of β-catenin, activated mTOR, and decreased autophagy in epithelial cells in co-culture. Our results demonstrate a HIF-1-dependent induction of Wnt1 in hypoxic macrophages that undermines autophagy in epithelial cells and suggest a role for Wnt signaling and mTOR pathways in the impaired epithelial autophagy observed in the mucosa of IBD patients.
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Ortiz-Masiá
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cosín-Roger
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Calatayud
authors.affiliation: FISABIO, Hospital Dr Peset, Valencia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Hernández
authors.affiliation: Hospital de Manises, Valencia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Alós
authors.affiliation: Hospital de Manises, Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Hinojosa
authors.affiliation: Universidad Jaume I, Castellón, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Apostolova
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Alvarez
authors.affiliation: Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: M D
authors.initials: MD
authors.lastname: Barrachina
mesh_terms: D000293:Adolescent; D000328:Adult; D001343:Autophagy; D015687:Cell Hypoxia; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495247:WNT1 protein, human; D051155:Wnt1 Protein; D058570:TOR Serine-Threonine Kinases