The emerging role of neutrophils in neonatal encephalopathy and hypoxic-ischemic brain injury: across human and animal neonates

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Abstract
Neutrophils, traditionally viewed as first responders to microbial invasion, also play a pivotal role in sterile inflammation associated with tissue injury or stress in the absence of pathogens. In this context, they are recruited by danger-associated molecular patterns (DAMPs) released from damaged or dying cells, rather than by microbial signals. Once at the site of injury, neutrophils clear debris, release proteases and reactive oxygen species contributing to tissue damage, and shape the inflammatory environment through cytokine and chemokine secretion. However, because their antimicrobial arsenal is nonspecific, their activity in sterile settings can be a double-edged sword: essential for initiating repair but also capable of exacerbating tissue injury if not properly regulated. Neutrophils have been implicated in many diseases of neonates, particularly neonatal encephalopathy (NE). Recently, this has been demonstrated using different hypoxic-ischemic encephalopathy (HIE) animal models. Harnessing the roles of neutrophils, both good and bad, can potentially influence future clinical therapies. This review summarizes the current knowledge about the role of neutrophils following perinatal hypoxic-ischemic brain injuries. Impact: This study elucidates the association between neutrophil activity and neonatal hypoxic-ischemic encephalopathy, thereby reinforcing emerging evidence from animal models and elucidating the underlying mechanisms of this prevalent neonatal condition. Neutrophils play a pivotal role in sterile inflammation, underscoring their dual function in both tissue repair and damage. This duality reshapes the understanding of injury, extending beyond the traditional focus on infection. Neutrophils have been recognized as potential therapeutic targets, and the modulation of their responses may achieve a balance between protection and injury. This approach could pave the way for novel, mechanism-based treatments for perinatal brain injury.

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