Reprogramming microglia in sepsis-associated encephalopathy: from pathological dysfunction to therapeutic restoration

Microglia, being the resident immunological sentinels of the central nervous system (CNS), play a critical role in both the pathogenesis and progression of CNS health and disease. In sepsis-associated encephalopathy (SAE), it is increasingly evident that the phenotype and function of microglia may change from a neuroprotective phenotype to a potential effector phenotype with neurotoxic potential. However, the exact mechanism by which this change is mediated remains to be understood. The current body of research is mostly focused on the hyperactivation of microglia, while the mechanism by which a pathological state develops from a systemic response remains to be understood. This limits the ability to design precise therapeutic strategies to target this cell population. In this regard, a framework of pathological state reprogramming is proposed to systematically evaluate potential mechanisms of microglial dysfunction in SAE. In this review, we will attempt to integrate the body of knowledge from single cell multi-omics, functional genetics, and in vivo imaging to determine the molecular characteristics of SAE-associated microglial states and potential functional alterations such as synaptic pruning. Further discuss the key factors that contribute to this evolution, such as inflammatory signaling, transcriptional and epigenetic regulation networks, and metabolic remodeling; and based on this basis, discuss multi-level therapeutic strategies for reversing the pathological state and restoring their protective role. These include potential strategies such as epigenetic and metabolic pathway modulation, CRISPR-mediated gene regulation, and cell therapies. These strategies consider microglia as a functional entity that has plasticity and can be modulated. The mechanistic basis developed in this review not only helps in understanding the pathology of SAE but also provides a basis for developing novel inflammatory modulation therapies for reversing the pathological state of microglia and restoring their protective surveillance role. This mechanistic basis for therapeutic innovation has a wide range of implications for developing intervention strategies for neuroinflammatory disorders.