title: Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia.
abstract: The neuronal guidance molecule netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1alpha (HIF-1alpha)-dependent induction of expression of the gene encoding netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, netrin-1 attenuated neutrophil transmigration. Exogenous netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1(+/-) mice relative to that in Ntn1(+/+) mice. Our studies demonstrate that HIF-1alpha-dependent induction of netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Tübingen 72076, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenberger
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schwab
authors.forename: Valbona
authors.initials: V
authors.lastname: Mirakaj
authors.forename: Eva
authors.initials: E
authors.lastname: Masekowsky
authors.forename: Alice
authors.initials: A
authors.lastname: Mager
authors.forename: Julio C
authors.initials: JC
authors.lastname: Morote-Garcia
authors.forename: Klaus
authors.initials: K
authors.lastname: Unertl
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009092:Mucous Membrane / Q000276:immunology / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000075388:Netrin-1; D020556:Neutrophil Infiltration / Q000276:immunology; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D018047:Receptors, Purinergic P1; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1