Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia.
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.
Rosenberger
Peter
P
Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Tübingen 72076, Germany.
Schwab
Jan M
JM
Mirakaj
Valbona
V
Masekowsky
Eva
E
Mager
Alice
A
Morote-Garcia
Julio C
JC
Unertl
Klaus
K
Eltzschig
Holger K
HK
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*
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