416: Msr1 in Microglia Activation and Sepsis-Associated Cognitive Impairment

Introduction: Sepsis-associated encephalopathy (SAE) is a frequent complication in ICU patients with sepsis, with over 25% of survivors experiencing lasting cognitive deficits. Effective treatments targeting SAE-related neurocognitive dysfunction remain lacking. Accumulating evidence indicates that aberrant activation of microglia plays a central role in SAE-associated neuroinflammation. While modulating microglial activation has shown therapeutic potential in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, its regulatory mechanisms in SAE remain unclear.To investigate the role of macrophage scavenger receptor 1 (MSR1), a class A receptor involved in phagocytosis and inflammation, in SAE pathogenesis. Methods: To explore MSR1’s role in SAE, we analyzed transcriptomic datasets to profile its CNS expression. MSR1 dynamics in microglia under septic conditions were examined using single-cell RNA-seq and in vivo LPS models. BV2 cells and mouse brain tissues were stimulated with LPS or poly(I:C) to assess MSR1 expression. Functional assays were performed after MSR1 knockdown or overexpression, including gene expression and phagocytosis-related analyses. Neuron–microglia co-culture systems evaluated microglia-mediated neurotoxicity. We also generated microglia-specific MSR1 knockout mice. Lastly, transcriptional studies identified upstream regulators of MSR1 expression. Results: We observed dynamic MSR1 expression changes in BV2 cells and mouse brain tissue after LPS and poly(I:C) stimulation. MSR1 knockdown or overexpression had minimal effects on TNF-α, IL-1β, and Arg1 expression but markedly altered phagocytosis- and complement-related genes, reversing LPS-induced microglial activation. In vitro co-culture confirmed MSR1 knockdown mitigated microglia-mediated neurotoxicity. Moreover, microglia-specific MSR1 knockout mice exhibited reduced 24-hour mortality post-LPS challenge. Mechanistically, while MAFB regulates basal MSR1 expression, it does not mediate its LPS-induced upregulation. Conclusions: This study identifies MSR1 as a key regulator of microglia activation, phagocytosis, and neuronal injury in SAE, providing new insights into the pathogenesis of SAE and offering a potential therapeutic target.