Abstract
Disrupted immune response is an important feature of many neurodegenerative conditions, including sepsis-associated cognitive impairment. Accumulating evidence has demonstrated that immune memory occurs in microglia, which has a significant impact on pathological hallmarks of neurological diseases. However, it remains unclear whether immune memory can cause subsequent alterations in the brain immune response and affect neurobehavioral outcomes in sepsis survivors. In the present study, mice received daily intraperitoneal injection of low-dose lipopolysaccharide (LPS, 0.1 mg/kg) for three consecutive days to induce immune memory (immune tolerance) and then were subjected to sham operation or cecal ligation and puncture (CLP) 9 months later, followed by a battery of neurobehavioral and biochemical studies. Here, we showed that repeated low-dose LPS injection-induced immune memory protected mice from sepsis-induced cognitive and affective impairments, which were accompanied by significantly decreased brain proinflammatory cytokines and immune response. In conclusion, our study suggests that modulation of brain immune responses by repeated LPS injections confers neuroprotective effects by preventing overactivated immune response in response to subsequent septic insult.
Highlights
Accumulating evidence has demonstrated that sepsis is a pivotal component in mediating cellular senescence, changes in neuronal plasticity, neuronal loss, and consequent cognitive impairments [1,2,3]
Animal studies have shown depressive-like behavior and learning and memory impairments after sepsis by lipopolysaccharide (LPS) challenge or cecal ligation and puncture (CLP) [4, 5]
Immune memory occurs in microglia and significantly affects pathological hallmarks of neurological disease in mouse models [7]
Summary
Accumulating evidence has demonstrated that sepsis is a pivotal component in mediating cellular senescence, changes in neuronal plasticity, neuronal loss, and consequent cognitive impairments [1,2,3]. Animal studies have shown depressive-like behavior and learning and memory impairments after sepsis by lipopolysaccharide (LPS) challenge or cecal ligation and puncture (CLP) [4, 5]. Dysregulated activation of trained immunity can lead to either hyperinflammation or immunodepression, indicating immune memory in microglia is highly plastic [8]. It has been shown that a single LPS injection induced immune training 1 day later, whereas repeated LPS injections for 4 consecutive days caused immune tolerance in the brain, as reflected by increased and decreased brain cytokine levels, respectively [8]. One recent study has shown that restoring the delicate balance of immune homeostasis confers substantial
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