Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model

Abstract

Higher levels of interleukin (IL)-6 and elevated neutrophil counts are consistently reported in the blood of patients with schizophrenia. Stressors during childhood and/or adolescence are major socioenvironmental risk factors for schizophrenia and may contribute to immune dysregulation. Previous studies using blood cytokines to stratify patients with schizophrenia suggest that only a subset presents a low-grade inflammatory state. However, these studies have not addressed whether environmental factors such as childhood maltreatment contributed to identifying inflammatory clusters. Moreover, a neutrophil-related mechanism (Neutrophil Extracellular Traps; NETs) central to both the initiation and chronicity of autoimmune and inflammatory diseases has never been investigated in psychiatry. Elevated NETs in schizophrenia may predispose patients to inflammatory and autoimmune diseases resulting in reduced life expectancy. We, therefore, investigated NETs as a novel mechanism and biological target in early schizophrenia and their role together with IL-6 and childhood maltreatment in identifying cluster subgroups. We found increased NETs in the plasma of patients with early schizophrenia (n = 78) compared to both their unaffected siblings (n = 25) and community controls (n = 78), irrespective of sex, body mass index, psychoactive drug use, or tobacco smoking. Increased NETs in patients were unrelated to antipsychotic treatment, which was further tested in vitro using fresh neutrophils. By applying unsupervised two-step clustering analysis, we integrated values of NETs, IL-6, and childhood maltreatment scores. We identified two main clusters; childhood maltreatment scores and NETs were the most important variables contributing to cluster separation (high-CL1 and low-CL2), while IL-6 was the least contributor. Patients allocated in the high-CL1 (61.5%) had significantly higher childhood maltreatment scores, NETs, and IL-6 levels than the remaining groups (patients low-CL2, siblings, and controls high-CL1 and low-CL2). We complemented these findings with a rat model based on stress exposure during adolescence that results in several schizophrenia-like changes in adulthood. We found that adolescent stressed rats had higher NETs and IL-6 levels in serum compared to non-stressed rats with a tendency to produce more NETs from the bone marrow. Altogether, this study brings a novel cellular-based mechanism in schizophrenia that, combined with early-stress, could be useful to identify subgroups for more personalised treatments.

Multivariate analyses of immune markers reveal increases in plasma EN-RAGE in first-episode psychosis patients

“…EN-RAGE is expressed by neutrophils and has pro-inflammatory effects by binding to advanced glycosylation end-product receptor (RAGE) that is present on target cells including the vasculature [ 17 ]. Our finding of elevated EN-RAGE in acute psychosis is in accordance with recent studies showing enhanced formation of neutrophil extracellular traps (NETs) in the blood of early schizophrenia [ 18 ]. We suggest that EN-RAGE and neutrophils may orchestrate the immune response and play an important role during the acute phase of psychosis.…”

“…Recently this issue was studied further by examining the degree of formation of neutrophil extracellular traps (NETs) that are present in various other inflammatory disorders [ 49 ]. Results showed an increase in NETs in schizophrenia patients compared with controls, indicating an involvement of neutrophils in the disease process [ 18 ]. This is in line with our present findings of higher EN-RAGE levels in acute psychosis as this protein is mainly produced by neutrophils in humans.…”

Altered neutrophil-to-lymphocyte ratio in patients with non-affective first episode psychosis and its relationship with symptom severity and cognitive impairment

“…A possible underlying mechanistic cellular-based involvement in the predisposition to inflammatory states has been fueled but a recent study which reported an increased blood neutrophil extracellular traps (NETs) in patients with early schizophrenia compared with controls irrespective of antipsychotic treatment. An early stress with history of childhood maltreatment also linked to patients with increased NETs 47 .…”