TWEAK receptor deficiency has opposite effects on female and male mice subjected to neonatal hypoxia-ischemia

Anton Kichev, Ana A. Baburamani, Regina Vontell, Pierre Gressens, Linda Burkly, Claire Thornton, Henrik Hagberg

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine member of the TNF family. TWEAK binds to its only known receptor, Fn14, enabling it to activate downstream signaling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signaling in neonatal hypoxia-ischemia (HI). We found that after neonatal HI, both TWEAK and Fn14 expression were increased to a greater extent in male compared with female mice. To assess the role of TWEAK signaling after HI, the size of the injury was measured in neonatal mice genetically deficient in Fn14 and compared with their wild-type and heterozygote littermates. A significant sex difference in the Fn14 knockout (KO) animals was observed. Fn14 gene KO was beneficial in females; conversely, reducing Fn14 expression exacerbated the brain injury in male mice. Our findings indicate that the TWEAK/Fn14 pathway is critical for development of hypoxic-ischemic brain injury in immature animals. However, as the responses are different in males and females, clinical implementation depends on development of sex-specific therapies.

Original languageEnglish (US)
Article number230
JournalFrontiers in Neurology
Issue numberAPR
StatePublished - Apr 12 2018
Externally publishedYes


  • Brain
  • Fn14
  • Hypoxia-ischemia
  • Perinatal brain injury
  • Sex differences
  • TweakR

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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