Microglial Reprogramming in Sepsis-Associated Encephalopathy: From Pathological Dysfunction to Therapeutic Recovery
Microglia, at the Frontier of the CNS
In sepsis-associated encephalopathy (SAE), microglia lose their protective role and undergo a shift toward toxic effects. Elucidating how systemic inflammation translates into a pathological state within the brain has been a major challenge.
Single-Cell Multi-Omics and Functional Genetics Open a New Path
Researchers combined single-cell multi-omics with functional genetics to trace the mechanisms underlying microglial transition. They identified not only hyperactivation of microglia but also reprogramming of metabolic and signaling pathways. Defining these causal relationships enabled the identification of precise therapeutic targets.
Future Therapeutic Strategies: Shifting Toward Reprogramming
The review proposes a pathological state reprogramming framework, suggesting that strategies can be designed to restore microglia to a protective phenotypic state. Ultimately, this could contribute to cognitive recovery and reduced mortality in SAE patients.
Implications and Outlook
If validated clinically, this approach could inaugurate a new therapeutic paradigm for preventing or reversing brain dysfunction in sepsis patients. Moreover, its applicability to other neuroinflammatory disorders may open a new era of central nervous system immune modulation.
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
Therapeutic interventions have been hampered by an incomplete understanding of the causes of acute cerebral dysfunction and long‑term cognitive impairment in sepsis patients. The microglial reprogramming strategy presented in this study offers a novel therapeutic option for preserving brain health.