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. 2025 Feb 10:1-10.
doi: 10.1159/000544063. Online ahead of print.

Growth Differentiation Factor-15 Knockout Mice Are Protected from Neonatal Hypoxic-Ischemic Injury in a Sex-Dependent Manner

Jeremy R Herrmann  1   2 , Patrick M Kochanek  3 , Vincent A Vagni  3 , Keri A Janesko-Feldman  3 , Jason P Stezoski  3 , Travis C Jackson  4
Affiliations

Growth Differentiation Factor-15 Knockout Mice Are Protected from Neonatal Hypoxic-Ischemic Injury in a Sex-Dependent Manner

Jeremy R Herrmann et al. Dev Neurosci. .

Abstract

Introduction: Neuroinflammation plays a critical role in tissue injury and repair after neonatal hypoxic-ischemic (HI) brain injury and varies by sex. Growth differentiation factor-15 (GDF-15) is a cytokine released by macrophages during inflammation and is upregulated after brain ischemia. We examined the impact of GDF-15 knockout (KO) on volume loss and the combined microglia/macrophage response in the Rice-Vannucci model of neonatal HI injury.

Methods: Male and female wild-type (WT) Gdf15+/+, heterozygous Gdf15nuGFP-CE/+ (Het), and homozygous Gdf15nuGFP-CE/nuGFP-CE (KO) mice were bred at the University of Pittsburgh. Postnatal day 9-11 mice were randomized to sham procedure or unilateral common carotid artery ligation followed by exposure to 8% O2 for 25 min. Pups were subsequently genotyped and survived for 14 days before sacrifice. Lesion volume and number of ionized calcium-binding adapter molecule 1 (Iba-1)-positive cells were quantified.

Results: Injured male KO pups had decreased hemispheric and hippocampal lesion volume versus injured male WT pups. Injured male Het pups demonstrated an intermediate phenotype. In males, the number of Iba-1-positive cells correlated with extent of tissue loss. In females, the extent of volume loss and Iba-1 cell counts post-injury did not vary by genotype.

Conclusion: GDF-15 exerts a sex-dependent deleterious effect on lesion volume in a neonatal HI model. Future work should identify how GDF-15 mediates different neuroinflammatory responses between sexes, establish if brain-secreted versus peripherally derived GDF-15 mediates the pro-injury phenotype that was inhibited in male KOs, and test if therapeutic inhibition of GDF-15 signaling is a novel treatment for neonatal HI brain injury.

Keywords: Asphyxia; Brain injury; Macrophage inhibitory cytokine-1; Neonatal encephalopathy; Neuroinflammation; Rice-Vannucci; Stroke.

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Conflict of interest statement

Competing Interests: The authors report no competing interests.

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