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

Nat Immunol. 2009 Feb;10(2):195-202. doi: 10.1038/ni.1683. Epub 2009 Jan 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Chemotaxis, Leukocyte / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression
  • Gene Expression Regulation / immunology*
  • Humans
  • Hypoxia / complications
  • Hypoxia / immunology
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / immunology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunoblotting
  • Immunohistochemistry
  • Immunoprecipitation
  • Inflammation / genetics
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Mice
  • Mucous Membrane / immunology
  • Mucous Membrane / metabolism
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / immunology
  • Nerve Growth Factors / metabolism*
  • Netrin-1
  • Neutrophil Infiltration / immunology
  • Receptors, Purinergic P1 / genetics
  • Receptors, Purinergic P1 / immunology
  • Receptors, Purinergic P1 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / immunology
  • Tumor Suppressor Proteins / metabolism*

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NTN1 protein, human
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Receptors, Purinergic P1
  • Tumor Suppressor Proteins
  • Netrin-1