Astrocytic LCN2 mediates pathological crosstalk with neurons to promote neuronal loss in sepsis-associated encephalopathy.

Lipocalin-2 (LCN2) has been implicated in the pathogenesis of sepsis-associated encephalopathy (SAE). Our previous work demonstrated a significant increase in astrocyte-derived LCN2 in the hippocampal region during SAE. Notably, this elevated expression strongly correlates with neuronal loss and cognitive impairment, although the underlying mechanisms remain elusive. In our study, we demonstrate that increased secretion of LCN2 from hippocampal astrocytes in SAE mice binds to the neuronal receptor 24p3R, thereby inducing neuronal damage. Notably, the downregulation of neuronal 24p3R effectively abolished the detrimental effects of LCN2. In both lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-induced sepsis models in C57 mice, neuronal 24p3R knockdown similarly alleviated sepsis-induced synaptic dysfunction and cognitive deficits. Moreover, elevated brain LCN2 levels during sepsis coincided with suppressed autophagy. Mechanistic studies revealed that LCN2-24p3R axis activated the neuronal mTOR-ULK1 pathway, leading to inhibition of autophagy. Importantly, the inhibition of neuronal mTOR activity restored autophagy and ameliorated mitochondrial damage and neuronal loss caused by astrocyte-derived LCN2. These findings suggest an etiopathogenic mechanism of SAE, which is initiated by the increased astrocytic secretion of LCN2, acting on neuronal 24p3R to activate the mTOR-ULK1 pathway, suppress autophagy, and promote mitochondrial dysfunction and neuronal loss, ultimately driving SAE progression. This study provides novel insights into the molecular mechanisms of astrocyte-neuron communication in SAE and identifies potential therapeutic targets for effective intervention.