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

Anton Kichev; Aradhna Baburamani; Regina Theresa Vontell; Pierre Gressens; Linda Burkly; Claire Thornton; Erik Gustaf Henrik Hagberg

doi:10.3389/fneur.2018.00230

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

Anton Kichev, Aradhna Baburamani, Regina Theresa Vontell, Pierre Gressens, Linda Burkly, Claire Thornton, Erik Gustaf Henrik Hagberg

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Abstract

Tumour 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 signalling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signalling 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 signalling 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 KO animals was observed. Fn14 gene knockout 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 language	English
Journal	Frontiers in Neurology
DOIs	https://doi.org/10.3389/fneur.2018.00230
Publication status	Published - 12 Apr 2018

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10.3389/fneur.2018.00230Licence: CC BY

TWEAK receptor deficiency has_KICHEV_Accepted23March2018_GOLD VoR (CC BY)Final published version, 7.42 MBLicence: CC BY

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title = "TWEAK receptor deficiency has opposite effects on female and male mice subjected to neonatal hypoxia-ischemia.",

abstract = "Tumour 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 signalling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signalling 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 signalling 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 KO animals was observed. Fn14 gene knockout 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. ",

author = "Anton Kichev and Aradhna Baburamani and Vontell, {Regina Theresa} and Pierre Gressens and Linda Burkly and Claire Thornton and Hagberg, {Erik Gustaf Henrik}",

year = "2018",

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doi = "10.3389/fneur.2018.00230",

language = "English",

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T1 - TWEAK receptor deficiency has opposite effects on female and male mice subjected to neonatal hypoxia-ischemia.

AU - Kichev, Anton

AU - Baburamani, Aradhna

AU - Vontell, Regina Theresa

AU - Gressens, Pierre

AU - Burkly, Linda

AU - Thornton, Claire

AU - Hagberg, Erik Gustaf Henrik

PY - 2018/4/12

Y1 - 2018/4/12

N2 - Tumour 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 signalling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signalling 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 signalling 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 KO animals was observed. Fn14 gene knockout 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.

AB - Tumour 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 signalling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signalling 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 signalling 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 KO animals was observed. Fn14 gene knockout 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.

U2 - 10.3389/fneur.2018.00230

DO - 10.3389/fneur.2018.00230

M3 - Article

SN - 1664-2295

JO - Frontiers in Neurology

JF - Frontiers in Neurology

ER -

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

Abstract

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