TREM2 regulates continual efferocytosis of apoptotic neurons by monocyte-derived macrophages via AKT-PFKFB2-mediated glycolytic reprogramming after acute ischemic stroke

Abstract

Efficient clearance of apoptotic neurons is crucial for mitigating secondary injury after acute ischemic stroke (AIS). Although monocyte-derived macrophages (MDMs) rapidly infiltrate the ischemic brain and upregulate triggering receptor expressed on myeloid cells 2 (TREM2) expression, whether and how TREM2 regulates the reparative efferocytic function of infiltrating MDMs remains elusive. Serum soluble TREM2 (sTREM2) levels and monocyte TREM2 expression were analyzed in patients with AIS. In a mouse model, ischemic stroke was induced by middle cerebral artery occlusion/reperfusion (MCAO/R). Infiltrating TREM2 + MDMs were characterized by flow cytometry, CCR2-GFP tracing, immunofluorescence, and adoptive transfer of TREM2-overexpressing bone marrow monocyte-derived macrophages (BMDMs). Single-cell RNA sequencing, metabolomic, and functional assays were used to investigate efferocytosis and its metabolic regulation. Human monocyte-derived macrophages (HMDMs) treated with the TREM2 agonistic antibody AL002c were used for translational validation. Patients with AIS exhibited elevated serum sTREM2 levels, which were positively associated with the National Institutes of Health Stroke Scale (NIHSS) score at admission and the modified Rankin Scale (mRS) score at 90 days. Concurrently, TREM2 expression was increased in circulating monocytes. In mice, infiltrating CCR2 + MDMs showed a marked upregulation of TREM2, myeloid TREM2 deficiency aggravated brain injury and neurological dysfunction, and adoptive transfer of TREM2-overexpressing BMDMs partially reversed these pathological changes. Mechanistically, in BMDMs, TREM2 promoted continual rather than first-round efferocytosis through SYK-dependent AKT–PFKFB2-mediated post-efferocytic glycolytic reprogramming, characterized by increased lactate availability and sustained MERTK and LRP1 expression. Notably, AKT signaling contributed to the TREM2-dependent regulation of apoptotic neuron clearance, neuroinflammation, infarct volume, and neurological recovery. In HMDMs, AL002c recapitulated the TREM2-dependent pathway and promoted a pro-resolving efferocytic phenotype. TREM2 promotes the continual efferocytosis of apoptotic neurons by MDMs and contributes to post-stroke repair through SYK-dependent AKT-PFKFB2-mediated glycolytic reprogramming, identifying TREM2⁺ MDMs as an important reparative population and a potential therapeutic target for AIS.