Abstract Number: Esoc2026a1971 Targeting Neutrophils to Protect Immune Competence and the Inflamed Brain After Stroke

Abstract Background and aims Ischemic stroke induces a biphasic immune pathology: an early hyper-immune activation phase followed by a state of severe systemic immunodeficiency. Our research identifies neutrophils as critical drivers of both phases after stroke. Notably, the existing comorbidities in stroke patients may fuel neutrophil activation and deteriorate disease outcomes. Results We recently showed that hypercholesterolemia promotes neutrophil cytokine release, neutrophil extracellular trap (NET) formation, and exacerbates inflammatory brain injury within a critical three-hour therapeutic window after stroke. Our new results demonstrate that swapping from a high-fat diet to a high-fiber diet can successfully reduce this early activation of neutrophils, possibly through gut microbiota-regulated pathways. Next, we discovered that early NET release after stroke caused extensive lymphocyte death and immunodeficiency in both experimental models and patients. This immune deficiency was associated with an increased pulmonary bacterial burden and was reduced by enzymatic digestion of NETs. In recent years, gut microbiota have been shown to regulate innate immunity. Our data showed that gut microbiota can intensively modify neutrophil responses after stroke. The depletion of gut microbiota induced a juvenile neutrophil phenotype with increased resting-state receptors, reduced inflammatory proteins, and NET formation. This decreased neutrophil reaction was related to reduced brain inflammation, fewer vascular thrombi, smaller infarcts, and improved functional recovery. Conclusions Together, these findings highlight early neutrophil activation as a key driver of post-stroke pathology. Targeting neutrophil responses within the acute phase may reduce brain injury, immunodeficiency, and bacterial infections in patients with cerebrovascular disease. Conflict of interest Vikramjeet Singh. nothing to disclose.