Exploring potential value of neutrophil extracellular traps in major depressive disorder

Abstract

Background: Neutrophil extracellular traps (NETs) can induce cellular and tissue damage through inflammatory responses. While the involvement of NETs in psychiatric disorders has shown preliminary potential, a systematic exploration of their link with major depressive disorder (MDD) is imperative. This study evaluated the clinical potential of three NET markers-myeloperoxidase (MPO)-DNA, neutrophil elastase (NE)-DNA, and citrullinated histones (citH3)-for diagnosing MDD and predicting treatment response.

Methods: Two independent clinical cohorts (Cohort 1: n=83; Cohort 2: n=60) and a chronic unpredictable mild stress (CUMS) mouse model were used. Physiotherapy and pharmacotherapy were administered to the two cohorts, respectively. NET markers were measured in plasma samples. Levels of NETs in the hippocampus were detected in CUMS mice. Pharmacological blockade of NET formation was performed in mice.

Results: (1) Independently validated across two cohorts, plasma levels of NET markers were significantly higher in MDD patients than in healthy participants. (2) In MDD patients, plasma NET markers significantly correlated with neuropsychological assessment scores, serum levels of inflammatory indices, and abnormal activation of the right calcarine and cuneus. (3) Relationship between NETs and C-reactive protein has an significant effect on depressive symptoms. (4) These NET markers could predict changes in 24-item Hamilton Depression Rating Scale scores after antidepressive treatments. (5) Compared with controls, CUMS mice exhibited significantly elevated levels of NE and MPO in the hippocampus. Preventing NET formation significantly reduced NE and MPO levels in plasma and hippocampus, and alleviated depressive-like behavior in CUMS mice.

Conclusions: Plasma NETs may be associated with the occurrence and progression of MDD, potentially via inflammatory mechanisms. Plasma NET markers may be used as valuable biomarkers to diagnose MDD and predict patient response to antidepressive treatment. Targeting NET formation could represent a potential therapeutic strategy for depression.

Keywords: antidepressive treatment; biomarker; inflammatory response; major depressive disorder; neutrophil extracellular traps.