Abstract
Sepsis could affect the central nervous system and thus induces neuroinflammation, which subsequently leads to brain damage or dysfunction. However, the mechanisms of generation of neuroinflammation during sepsis remain poorly understood. By administration of lipopolysaccharides (LPS) in mice to mimic sepsis, we found that shortly after opening the blood–brain barrier, conventional CD11b+CD27+ NK subset migrated into the brain followed by subsequent neutrophil infiltration. Interestingly, depletion of NK cells prior to LPS treatment severely impaired neutrophil recruitment in the inflamed brain. By in vivo recruitment assay, we found that brain-infiltrated NK cells displayed chemotactic activity to neutrophils, which depended on the higher expression of chemokines such as CXCL2. Moreover, microglia were also responsible for neutrophil recruitment, and their chemotactic activity was significantly impaired by ablation of NK cells. Furthermore, depletion of NK cells could significantly ameliorate depression-like behavior in LPS-treated mice. These data indicated a NK cell-regulated neutrophil recruitment in the blamed brain, which also could be seen on another sepsis model, cecal ligation and puncture. So, our findings revealed an important scenario in the generation of sepsis-induced neuroinflammation.
Highlights
Sepsis could affect the central nervous system and induces neuroinflammation, which subsequently leads to brain damage or dysfunction
To investigate whether LPS-induced inflammation spread into the CNS, we first examined the integrity of blood–brain barrier (BBB) by using Evans Blue i.v. injection
By scanning the expression of rate-limiting enzymes for neurotransmitter metabolism using qPCR, we found significant changes on the expression of serotonin metabolism-associated enzymes and proteins including tryptophan hydroxylase 2 (TPH2), monoamineoxidase (MAO-A) and serotonin transporter (SERT) in the brain from mice treated with LPS for 3 days (Fig. 7a)
Summary
Sepsis could affect the central nervous system and induces neuroinflammation, which subsequently leads to brain damage or dysfunction. Depletion of NK cells could significantly ameliorate depression-like behavior in LPS-treated mice These data indicated a NK cell-regulated neutrophil recruitment in the blamed brain, which could be seen on another sepsis model, cecal ligation and puncture. In the model of cecal ligation and puncture (CLP), mice with NK cell depletion were protected against sepsis-induced mortality[7] This is associated with the migration of NK cells from blood and spleen to the inflamed peritoneal cavity, where they promote the proinflammatory activities of myeloid cell populations[8]. In the animal model to mimic sepsis, we here observed the regulation of inflammation by NK cells in the brain, where CNS-infiltrated NK cells recruited neutrophils by producing chemokines and promote neutrophil recruitment via modulating microglia.
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