Hypoxia-inducible factor–dependent induction of netrin-1 dampens inflammation caused by hypoxia

P Rosenberger, JM Schwab, V Mirakaj… - Nature …, 2009 - nature.com
P Rosenberger, JM Schwab, V Mirakaj, E Masekowsky, A Mager, JC Morote-Garcia, K Unertl…
Nature immunology, 2009nature.com
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) …
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 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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