Work

Formyl peptide receptor 1 signaling exacerbates hemorrhagic transformation following tPA thrombolysis in mice

Year: 2025

Type: article

Abstract: Hemorrhagic transformation (HT) is a severe complication occurring in ischemic stroke patients undergoing tPA thrombolytic therapy, which significantly limits its clinical applicability. The mechanism and intervention of HT is still not fully understood. In our study, we found that an increased mobilization of circulating formyl peptide receptor 1 (FPR1) expressing leucocytes into the ischemic brain after tPA treatment in mice. In Fpr1 −/− mice, neutrophil mobilization and HT occurrence after tPA thrombolysis decreased. Notably, pharmacological inhibition of FPR1 using a novel antagonist T0080 effectively mitigated tPA-associated HT, concurrently reducing neutrophil infiltration into the brain and preserving blood–brain barrier (BBB) integrity. We further revealed that brain infiltration neutrophils facilitate BBB leakage and neuron death by producing cytotoxic molecules such as reactive oxygen species (ROS), matrix metalloproteinase-9 (MMP9), and tumor necrosis factor-alpha (TNF-α). Neutrophil depletion and adoptive transfer experiments in vivo with FPR1 + neutrophils demonstrate that the essential role of FPR1 + neutrophils in mediating HT post-tPA administration in mice. Collectively, these findings identify neutrophils FPR1 activation as a key mechanistic driver exacerbating HT following tPA thrombolysis in ischemic stroke.

Source: Journal of Cerebral Blood Flow & Metabolism

DOI: 10.1177/0271678x251392044