Targeting HPK1 inhibits neutrophil responses to mitigate post-stroke lung and cerebral injuries.

Abstract

Circulating neutrophils are responsible for poor neurological outcomes and have been implicated in respiratory morbidity after acute ischemic stroke (AIS). However, the molecular mechanisms regulating neutrophil responses and their pathological relevance in post-stroke complications remain unclear. In this study, we investigated the involvement of hematopoietic progenitor kinase 1 (HPK1) in neutrophil responses and mobilization, as well as subsequent lung and cerebral injuries following AIS. We found that lipopolysaccharide treatment triggered neutrophil activation in an HPK1-dependent manner. HPK1 enhanced intrinsic NF-κB/STAT3/p38-MAPK pathways and gasdermin D cleavage, leading to neutrophil hyperactivation. Following AIS, HPK1 promoted the mobilization of CXCR2^high bone marrow neutrophils. HPK1 loss inhibited peripheral neutrophil hyperactivation, neutrophil infiltration, and aggregation of neutrophil extracellular traps, progressively alleviating systemic inflammation and impairments in mouse pulmonary and neurological functions. Furthermore, HPK1 pharmacological inhibition attenuated post-stroke pulmonary and neurological impairments in mice. Our findings revealed that HPK1 upregulates neutrophil mobilization and various responses, promoting post-stroke systemic inflammation and tissue injury. This study highlights HPK1 as a therapeutic target for improving pulmonary and neurological functions after AIS.