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

Peter Rosenberger, Jan M Schwab, Valbona Mirakaj, Eva Masekowsky, Alice Mager, Julio C Morote-Garcia1, Klaus Unertl1 & Holger K Eltzschig,

Nature Immunology 10, 195-202. (2009)

Speaker: Yu-Hong Chen (陳俞宏)                                        Time: 13:10~14:00 May. 20, 2009

Commentator: Dr. Chrong-Reen Wang (王崇任醫師)         Place: Room 601

Abstract:

Transcription factor hypoxia-inducible factor 1 (HIF-1) has been suggested to be involved in regulating anti-inflammation signaling pathway during hypoxia^{1, 2}. Recent studies have shown the neuronal guidance molecule netrin-1 is able to attenuate inflammation³. The authors sought to determine the immunomodulatory function of the netrin-1 in hypoxia. Since the large surface areas of mucosal organs such as lung and intestine are particularly prone to hypoxia-induced inflammation². The authors used immunostaining and immunohistological staining to confirm netrin-1 was induced by hypoxia on the mucosal surfaces in vitro and in vivo. They also analyzed NTN1 promoter to show that HIF-1α directly regulates netrin-1 expression during hypoxia. In agreement with the role of neutrophils in inflammation, the authors found that netrin-1-dependent signaling through the adenosine receptor A2BAR not only attenuate neutrophil transepithelial migration but also modulate intracellular cAMP production and membrane permeability during hypoxia-induced inflammation. Moreover, in bone marrow-chimeric mice, A2BAR expressed on hematopoietic cells in the netrin-1-dependent attenuation of hypoxia-induced inflammation in vivo. Finally, the authors assessed the function of endogenous netrin-1 in regulating hypoxia-induced inflammation in Ntn^+/- mice. Ntn^+/- mice were in a relative serious inflammatory situation, and that could be restored to wild-type phenotype by treating with A2BAR agonist (BAY 60-6583). In summary, HIF-1α-dependent induction of netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.

References:

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2. Karhausen, J., Ibla, J.C. & Colgan, S.P. Implications of hypoxia on mucosal barrier function. Cell. Mol. Bio. 49, 77–87 (2003).

3. Ngoc P. Ly, Katsumi Komatsuzaki, Iain P. Fraser, Anita A. Tseng, Parthak Prodhan, Kathryn J. Moore, and T. Bernard Kinane. Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc. Natl. Acad. Sci. USA 102, 14729–14734 (2005).