The Role of Neutrophil Extracellular Traps in Lipopolysaccharide-Induced Depression-like Behaviors in Mice

Peripheral inflammation plays a key role in the development of depression-like behaviors. However, the mechanisms underlying these effects remain largely unknown. Here, we found that the level of citrullinated histone H3 (cit-H3) significantly increased in the plasma of wildtype mice treated with lipopolysaccharide (LPS), which indicated that neutrophil extracellular traps (NETs) were formed. Moreover, the LPS-induced depression-like and asocial behaviors were significantly alleviated in the mice deficient of NETs. Mechanistically, NETs formation aggravated peripheral inflammation by increasing the concentrations of TNF-alpha, IL-1 beta and IL-6 in plasma, which are major proinflammatory cytokines that can enter the brain, resulting in microglia activation and reduced astrocytes. Following this, increased TNF-alpha and IL-1 beta were released into brain, inducing neuroinflammation and finally depression-like behaviors. Prohibiting NETs by PAD4 ablation significantly prevented LPS-induced microglia activation and the loss of astrocytes. Our results propose the role for peripheral NETs in LPS-induced depression-like behavior, and that NETs might be a potential target to prevent inflammation-induced major depressive disorder.