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

Nature Immunology volume 10, pages 195–202 (2009)Cite this article

A Corrigendum to this article was published on 21 April 2015

This article has been updated

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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Figure 1: Induction of netrin-1 by hypoxia.
Figure 2: Influence of hypoxia on the NTN1 promoter.
Figure 3: Effect of netrin-1 on transepithelial PMN migration.
Figure 4: Netrin-1 in an A2BAR signaling model.
Figure 5: Effect of exogenous netrin-1 on inflammatory hypoxia in vivo.
Figure 6: Effect of endogenous netrin-1 on inflammatory hypoxia in vivo.

Change history

  • 27 February 2015

    In the version of this article initially published, the contrast in lane 4 of Figure 2c had been altered, and the top right image in Figure 5a and bottom right image Figure 6e were incorrect. The correct gel and images are now presented. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Tübingen, 72076, Germany

    Peter Rosenberger, Valbona Mirakaj, Eva Masekowsky, Alice Mager, Julio C Morote-Garcia, Klaus Unertl & Holger K Eltzschig

  2. Department of Neurology and Experimental Neurology, Charite, School of Medicine, Humboldt University, Berlin, 10098, Germany

    Jan M Schwab

  3. Department of Anesthesiology, Mucosal Inflammation Program, University of Colorado Health Sciences Center, Denver, 80045, Colorado, USA

    Holger K Eltzschig

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Contributions

P.R. did most in vitro and all in vivo experiments, analyzed and interpreted the data, and wrote parts of the manuscript; J.M.S. provided the initial idea, helped with the design of the research and interpretation of data; V.M. helped with in vivo studies and data analysis; E.M. did part of the in vitro studies; A.M. studied cAMP responses elicited by netrin-1; J.C.M.-G. helped with in vivo studies; K.U. helped with data interpretation, reviewed the manuscript and helped with writing; and H.K.E. designed the research and wrote the manuscript.

Note: Supplementary information is available on the Nature Immunology website.

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Correspondence to Holger K Eltzschig.

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Supplementary Figures 1–4, Tables 1–4 and Supplementary Methods (PDF 434 kb)

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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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