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 1α (HIF-1α)-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-1α-dependent induction of netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.
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We thank M. Faigle, D. Köhler and S. Laucher for technical support; Bayer Healthcare for BAY 60-6583; and S.P. Colgan (University of Colorado Denver), M. Tessier-Lavigne (Genentech) and C. Ledent (Université Libre de Bruxelles) for breeding pairs of gene-targeted mice. Supported by the University of Tübingen (Fortüne grants 1639-0-0 to P.R. and 1778-0-0 to V.M.), Deutsche Forschungsgemeinschaft (EL 274/2-1 to H.K.E., and EL 274/2-1 and RO 3671/2-1 to P.R.) and the Foundation for Anesthesia Education and Research (H.K.E.).
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Rosenberger, P., Schwab, J., Mirakaj, V. et al. Hypoxia-inducible factor–dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat Immunol 10, 195–202 (2009). https://doi.org/10.1038/ni.1683
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