Downregulation of RACK1 promotes LPS-induced neuronal necroptosis contributes to sepsis-associated encephalopathy in mice

BackgroundSepsis-associated encephalopathy (SAE) is a frequent severe complication of surviving sepsis patients, associated with persistent cognitive impairments. Even though neuronal activity strongly impacts the functionality of the limbic system, the specific prevention and therapy for SAE remain limited since its underlying network mechanisms are still poorly understood.MethodsReceptor for activated protein kinase C 1 (RACK1) siRNA was transfected in SH-SY5Y and systemic LPS injection-induced depressive and anxiety-like behaviors mice model to evaluate the potential contribution of endogenous RACK1 in response to systemic LPS-induced neuronal necroptosis. Molecular docking and co-immunoprecipitation were employed to explore the relationship between RACK1 and RIPK1. The neuroprotective effect and molecular mechanism of Tanshinone IIA (Tan IIA) on neuronal necroptosis was explored through behavioral tests, histopathological analysis, and western blotting.FindingsHippocampal RACK1 protein expression was downregulated and associated with systemic LPS injection-induced depressive and anxiety-like behaviors in mice. The knockdown of RACK1 promotes systemic LPS-induced depressive and anxiety-like behaviors and neuronal necroptosis in mice and contributes to potentiating the LPS-associated activation of MLKL. LPS induced the RACK1/RIPK1 complex formation in neurons. Tan IIA significantly improved systemic LPS-induced cognitive impairments in mice through the upregulation of RACK1, suppressing neuronal necroptosis. Mechanically, Tan IIA promoted the formation of the RACK1/RIPK1 complex in neurons, thus inhibiting TNFR-triggered necroptosis.InterpretationEndogenous RACK1 is the critical protective factor in the limbic system against neuronal necroptosis and improves long-term cognitive dysfunction in SAE. Additionally, Tan IIA protects the septic-associated neurocognitive function by inhibiting neuronal necroptosis via upregulating RACK1 in the limbic system.