Downregulation of PDCD4 contributes to microglial efferocytosis and neurological function recovery following intracerebral hemorrhage

Efferocytosis plays a vital role in mitigating inflammation and subsequent tissue damage by clearing dying cells after intracerebral hemorrhage, but its underlying mechanism remains poorly understood. In this study, programmed cell death 4 (PDCD4) exhibited upregulated expression and localization to microglia following intracerebral hemorrhage. Targeted adenoviral-mediated Pdcd4 knockdown in vivo markedly improved neurological recovery and enhanced microglial efferocytosis in intracerebral hemorrhage model mice. These effects were further validated in Pdcd4 knockout mice. In an in vitro intracerebral hemorrhage model using oxyhemoglobin-treated microglia, Pdcd4 knockdown notably increased the expression of efferocytosis-related molecules AXL receptor tyrosine kinase (AXL) and MER proto-oncogene, tyrosine kinase (MERTK). Mechanistically, an interaction between PDCD4 and signal transducer and activator of transcription 3 (STAT3) identified under basal conditions was amplified following intracerebral hemorrhage. Pdcd4 knockdown also promoted Janus kinase 2 (JAK2)-mediated STAT3 phosphorylation and nuclear translocation, driving Mertk and Axl transcription to facilitate microglial efferocytosis. Furthermore, Pdcd4 knockdown markedly reduced proinflammatory factor expression while enhancing anti-inflammatory factor levels, thereby mitigating the neuronal apoptosis induced by conditioned medium. These findings indicate that PDCD4 blockade enhances microglial efferocytosis by activating the JAK2-STAT3-Mertk/Axl pathway and promotes post-intracerebral hemorrhage neurological recovery, identifying PDCD4 as a potential therapeutic target.