Impact of peripheral immune cells in experimental neonatal hypoxia-ischemia: A systematic review and meta-analysis

•Brain infiltration of leukocytes is a key factor in neonatal hypoxia–ischemia pathology.•Multiple leukocyte subtypes infiltrate the neonatal brain following hypoxia–ischemia.•Leukocyte infiltration is more pronounced in males compared to females after hypoxia–ischemia.•The mechanisms driving peripheral immune cell infiltration into the brain exhibit sexual dimorphism. Infiltration of peripheral immune cells into the brain following neonatal hypoxia–ischemia (HI) contributes to increased neuroinflammation and brain injury. However, the specific roles of different immune cell types in neonatal brain injury remain poorly understood. Although existing evidence suggests a potential role for sexual dimorphism in HI outcomes, this aspect has been insufficiently investigated. In this systematic review and meta-analysis, we examined the brain infiltration of peripheral immune cells in rodents of both sexes following neonatal HI. A total of 25 studies were included. Our analysis revealed significant increases in the infiltration of various subtypes of leukocytes after HI, along with increased brain injury, cell death, and neuroinflammation, and reduced neuronal survival. Notably, males exhibited a greater degree of immune cell infiltration and more pronounced neuroinflammation compared to females. These findings suggest that infiltrating leukocytes contribute significantly to the pathophysiology of neonatal HI, with sexually dimorphic responses further influencing the outcomes. It is crucial that future research focuses on elucidating the specific roles of immune cell subtypes to better understand the mechanisms underlying brain damage after HI and identify novel therapeutic targets. Moreover, the observed sex differences highlight the need to consider sex as a key factor when developing strategies for the treatment of neonatal HI.