Research Progress on Sepsis-Associated Encephalopathy and Macrophages: from Pathological Mechanisms to Precision Therapy
DU Deren, HUANG Qian*
SAE (sepsis-associated encephalopathy) is the most common and severe neurological complication of sepsis, with high incidence and long-term cognitive impairment frequently observed in survivors. Its pathogenesis involves complex mechanisms including systemic inflammatory response, blood-brain barrier disruption, neuroinflammatory cascade amplification, oxidative stress, and gut-brain axis dysregulation. Macrophages/microglia serve as the core node connecting peripheral immunity with the central nervous system and play a pivotal role in SAE pathogenesis. This review systematically summarizes the pathophysiological mechanisms of SAE, highlighting the central role of microglia in neuroinflammation initiation, blood-brain barrier disruption, synaptic plasticity impairment, and gut-brain axis regulation. This study also reviews precise therapeutic strategies targeting microglia, including microglial depletion, suppression of microglial activation and pyroptosis, and modulation of cGAS-STING, EZH2-AKT2, RasGRP1, and PDK4/NLRP3 signaling pathways. Furthermore, this review analyzes the current status of clinical biomarkers for SAE diagnosis and the challenges in clinical translation of targeted therapies, such as blood-brain barrier permeability, therapeutic time window, cell specificity, and patient heterogeneity. Future research should leverage single-cell multi-omics to elucidate microglial heterogeneity, develop specific targeted delivery systems, and conduct rigorous randomized controlled trials to provide novel strategies for precise diagnosis and treatment of SAE.
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