CRC TRR 332 - B02: Intracellular signalling mechanisms for neutrophil reactivity in acute ischemic stroke – implications for post-stroke systemic inflammation

Basic data for this project

Description

NR4A1 is a transcriptional checkpoint that restrains neutrophil activation after cerebral ischemia. In murine models, neutrophil-specific NR4A1 deletion exacerbated infarct size and worsened neurological outcome, whereas pharmacological activation reduced damage and improved recovery in a bicentric preclinical trial. In stroke patients, higher acute NR4A1 expression in neutrophils correlated with favourable three-month outcome, underscoring its translational relevance. Beyond neuroinflammation, neutrophils are the dominant source of circulating cell-free DNA (cfDNA) after stroke, a potent DAMP that amplifies systemic inflammation and vascular comorbidities. NR4A1 suppresses inflammasome activation by binding the NACHT domain of NLRP3, thereby limiting caspase-1 activity, IL-1β release, and downstream proinflammatory gene expression (IL-1α/β, IL-6, Nos2). Loss of NR4A1 amplifies these pathways, reinforcing its role as a broad anti-inflammatory regulator. In the next phase, we define early systemic neutrophil activators post-stroke, dissect how NR4A1 controls inflammasome signalling and NETosis, map neutrophil subpopulations in human stroke, and link NR4A1 expression to patient outcome. These studies aim to establish NR4A1 as a therapeutic target to modulate systemic inflammation and extend treatment opportunities beyond recanalization.