Neutrophil heterogeneity and crosstalk with cerebral-resident cells: therapeutic targets for ischemic stroke

Acute ischemic stroke elicits a robust inflammatory response within the brain. As one of the first peripheral immune cells to infiltrate the ischemic parenchyma, neutrophils show high heterogeneity and engage in complex crosstalk with resident brain cells. In this review, we first delineate the temporal dynamics of neutrophil mobilization after ischemic stroke, emphasizing their early and sustained accumulation in the ischemic brain. We then highlight recent advances in understanding neutrophil heterogeneity following ischemic stroke, with a particular focus on the skull–brain axis revealed by single-cell RNA sequencing. Additionally, we discuss the multifaceted interactions between neutrophils and parenchymal cells, including endothelial cells, neurons, microglia, and astrocytes after ischemic stroke. Finally, we expand the translational perspective by discussing emerging therapeutic approaches targeting neutrophils, NETosis, or specific neutrophil subsets in ischemic stroke. Unlike prior reviews that broadly focused on inflammatory networks, the present review specifically emphasizes the crosstalk between distinct neutrophil subsets and cerebral-resident cells, and integrates the latest single-cell RNA sequencing discoveries, including the newly identified skull–brain axis and a critical discussion of dichotomous models. Collectively, a comprehensive understanding of this intricate cellular network may help elucidate neutrophil heterogeneity, and future therapeutic strategies should shift from broad neutrophil depletion to precise targeting of pathogenic subsets to preserve potential repair functions.