Abstract
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-α, IL-1β 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-α and IL-1β 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.
Highlights
Major depressive disorder (MDD) ranks as the first cause of disability all over the world, and more than 300 million people suffer from this devastating disorder [1]
Multiple clinical studies have shown that MDD patients have more C-reactive protein (CRP), proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α in the blood than the healthy controls [3,4,5]
Neutrophils were extracted from the peripheral blood and stained with myeloperoxidase (MPO), which was presented in neutrophil extracellular traps (NETs)
Summary
Major depressive disorder (MDD) ranks as the first cause of disability all over the world, and more than 300 million people suffer from this devastating disorder [1]. Even though multiple effective treatments for MDD are accessible, about one third of patients achieve little remission following treatment [2], contributing to the global disease burden. Multiple clinical studies have shown that MDD patients have more C-reactive protein (CRP), proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α in the blood than the healthy controls [3,4,5]. Suicide victims with depression showed higher levels of IL-1β, IL-6 and TNF in postmortem brains, while the receptors for the production of these cytokines, such as Toll-like receptor 3 (TLR3) and TLR4, were affected [7,8,9]. Some depression patients undergo inflammation alteration and cytokines, which attract more and more attention and have been studied extensively, but
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