Potential role between inflammatory cytokines and Tie-2 receptor levels and clinical symptoms in patients with first-episode schizophrenia

Schizophrenia (SCZ) is a common, severe mental disorder of unknown etiology that affects approximately 1% of the world’s population [1, 2]. It usually begins in early adolescence and is characterized by disorganized thinking, lack of motivation, emotional apathy, and cognitive impairment [3]. Previous studies have identified SCZ as a neurodevelopmental disorder caused by pro-inflammatory risk genes, environmental stress factors, and immune system alterations [4, 5]. The vulnerability–stress–inflammation hypothesis could help explain the key role of inflammation in SCZ. Stress may increase the expression of pro-inflammatory cytokines and thereby contribute to the development of SCZ symptoms [6, 7]. However, current evidence on the relationship between inflammation and SCZ pathogenesis is heterogeneous and uncertain, which could imply that the present literature has inadequately accounted for the effect of confounding factors on the mechanisms underlying SCZ. Thus, further novel evidence is needed to identify the link between the immune system and SCZ and to provide useful suggestions for future research or improvements. Indeed, resurgent interest in this research area has arisen in recent years.

Inflammation is the first step in the immune response [8]. Well-regulated inflammatory processes are crucial for the homeostasis and normal function of tissues. Excessive inflammatory responses can lead to host cell damage [9]. Cytokines are key molecules in the regulation of inflammation and are important mediators between the brain and the immune system. Cytokines can affect neurodevelopmental, neuroendocrine, and neurotransmission processes through inflammatory immune responses, leading to structural or functional brain damage and thereby contributing to SCZ psychopathology [10]. Increasing evidence has demonstrated that cytokines, such as interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α, cause changes in the peripheral blood of patients with SCZ [10, 11]. Numerous studies have shown that the use of anti-inflammatory drugs as adjuncts to antipsychotics is superior to a placebo in SCZ patients [12], providing evidence for immune-based therapy for symptom improvement. However, inconsistent conclusions have been drawn regarding the effects of abnormal expression of inflammatory cytokines on SCZ symptoms due to dissimilarities in the clinical SCZ status of patients.

In addition, inflammation is associated with increased vascular risk and contributes to the subsequent development of hypertension, atherosclerosis, and ischemic stroke [13‐15]. Notably, cardiovascular disease risk is significantly higher in patients with SCZ than in the general population [16, 17]. Maladaptive and persistent inflammatory responses may be linked to the development and maintenance of cardiovascular diseases in SCZ [18]. Endothelial tyrosine kinase receptors with immunoglobulin and epidermal growth factor homology domain 2 (Tie-2) play a key role in inflammation-related pathological angiogenesis and inflammatory processes [19]. The function of Tie-2 and inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, in vascular inflammation has been verified in tumor angiogenesis, retinal angiogenesis, arthritis, and peripheral artery diseases [19‐23]. However, to date, no study has simultaneously reported the levels of Tie-2 and inflammatory cytokines in patients with first-episode SCZ.

In this study, we investigated whether serum inflammatory cytokines and Tie-2 receptor levels were altered in first-episode SCZ patients and explored the relationship between cytokines and Tie-2 receptor levels and psychopathological symptoms, to provide new feasible ideas for clinical intervention and assessing prognosis in SCZ.

We found that IL-1β and IL-4 levels were significantly elevated in first-episode psychosis in patients diagnosed with SCZ. This result was consistent with some previous studies [30‐33], but not with those of others [34‐37]. We did not find statistically significant differences in IL-6, IL-10, and TNF-α levels between the case group and healthy controls, similar to some published studies [30, 35, 38]. However, several studies, including meta-analyses, found elevated levels of IL-6, IL-10, and TNF-α in first-episode drug-naïve (FEDN) psychosis patients and first-episode SCZ patients, the majority of whom were using antipsychotics [30‐32, 37]. Conversely, Goldsmith, as well as Xiu et al., found reduced levels of IL-10 in first-episode SCZ patients and FEDN patients [30, 39], while another study showed that TNF-α levels were reduced in FEDN patients [40].

Furthermore, the BPRS total scores, resistance subscores, and PANSS positive subscores were positively correlated with IL-1β levels. These findings were consistent with those of a previous study [32]. Further stepwise linear regression analysis also showed that IL-1β levels were significantly associated with positive symptoms and the total scale score. Our results suggested that the increase in IL-1β levels may fluctuate over time and may synchronize with the worsening of symptoms; however, longitudinal studies are required to evaluate this hypothesis. Studies have shown that the positive symptoms of SCZ are mainly related to the overactivation of dopaminergic neurons in the mesolimbic system [41]. It has been shown that the number of dopaminergic neurons in the fetal brain increases after early infection or in the presence of maternal immune stimulation during pregnancy [42]. IL-1β induces the differentiation of mesencephalic-derived progenitor cells into dopaminergic neurons [43, 44] and induces continuous hippocampal inflammation, leading to severe depletion of developing neuroblasts and skewing of the fate of neural progenitor cells in the dentate gyrus of the hippocampus [45]. IL-1β mRNA levels have also been found to be associated with decreased Broca-area volume and verbal fluency in SCZ [46]. These studies indicated that pro-inflammatory cytokines have important effects on neurotransmitter systems, neurogenesis, and neurodevelopment in SCZ patients. Combined with these findings, our results suggest that IL-1β may be involved in pathophysiological changes leading to first-episode SCZ, and that baseline levels of IL-1β may serve as biomarkers for evaluating the severity of positive symptoms in patients with first-episode SCZ.

Tie-2, the homologous receptor for angiogenin-1 and -2 (Ang1 and Ang2), is a transmembrane tyrosine kinase receptor that is predominantly expressed in vascular endothelial cells and controls angiogenesis and vascular remodeling [47]. Aside from its vascular functions, Tie-2, particularly the Tie-2/Ang signaling axis, plays an important role in inflammatory processes. Previous studies have shown that Tie2/Ang-2 signaling induces the expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 and promotes leukocyte adhesion and transport to inflamed tissues in response to inflammatory cytokines [48, 49]. Macrophage Tie-2 signaling can promote a pro-inflammatory environment by inducing the production of IL-6 and the chemokine macrophage inflammatory protein 1α, while antagonizing this pathway can reduce inflammatory responses [50]. Others have previously demonstrated that Ang-2 contributes to establishing an overall immunosuppressive environment via upregulation of IL-10 by Tie-2-expressing monocytes/macrophages (TEMs) and by regulation of T cell expansion [50]. In addition, one study showed that the mRNA and protein levels of Tie-2 are decreased in lipopolysaccharide-induced inflammatory responses in mice [20]. Another study found a reduced number of TEMs in the peripheral blood circulation during an inflammatory state [20, 51]. In our study, we revealed that Tie-2 expression is reduced in patients with first-episode SCZ as compared to that in healthy controls. Tie-2 expression in vivo depends on the blood flow. Vasodilation, which occurs during inflammation in relation to the decrease in endothelial shear stress, reduces Tie-2 expression; however, the regulatory mechanism in inflammation remains to be studied [52]. Combined with the above research, our results suggest that SCZ is associated with chronic low-grade inflammation.

Clinical trials have confirmed that inflammation is causally involved in atherosclerotic events in humans. Recently, increased IL-1 activity has been associated with increased risk and severity of cardiovascular diseases [53]. Low Tie-2 receptor expression may lead to vascular complications associated with infection and inflammation [54]. Significantly, cardiovascular disease is two-fold higher in people with SCZ than in the general population and is the main reason for a shortened life expectancy and death among patients with SCZ [16, 17]. Moreover, compared with psychotic symptoms or disease duration, negative SCZ symptoms have a higher degree of impact on the increased risk of cardiovascular disease in these patients [55]. Our results showed that low Tie-2 receptor expression in the case group was significantly and positively correlated with negative symptoms. Although few clinical studies have supported the Tie-2 receptor as a diagnostic marker, various inflammatory cytokines, including TNF-α, IL-1β, and IL-11, influence Tie-2 receptor expression, making analysis of this receptor an attractive method for predicting vascular disease [52, 56]. Consistent with previous studies, our study showed a significant correlation between Tie-2 expression and IL-1β levels. Additionally, the results of the ROC analysis suggested that IL-1β and Tie-2 had high specificity and sensitivity for predicting the progression of clinical symptoms in the case group. Therefore, we speculate that patients with first-episode SCZ may have inflammation-related pathological angiogenesis, which is related to the occurrence and development of cardiovascular disease. The Tie-2 receptor may be an important predictor of increased cardiovascular risk caused by negative symptoms in patients with SCZ. Nevertheless, it remains unclear whether the changes in Tie-2 expression are the outcome of changes in cytokine levels or are caused by a vascular inflammatory response in patients with SCZ. Therefore, further research is needed to solve this problem comprehensively.

Considering the research methods related to inflammation-associated cytokine levels, as compared with the traditional methods of ELISA and Luminex assays, is worthwhile. The main advantage of the present study is that we used MSD to measure the level of inflammatory cytokines. This method is more sensitive, accurate, and precise. Our study had the following limitations: First, the cross-sectional design of this study limited our causal inferences regarding the role of inflammatory cytokines and Tie-2 in first-episode SCZ patients. Prospective longitudinal studies are required to obtain more accurate causal information on disease risk predictors in the future. Second, the sample size in the present study was relatively small; thus, future studies should target larger cohorts of SCZ patients. Third, to avoid drug interference with the research results, we recruited FEDN SCZ patients. However, it is noteworthy that antipsychotic drugs are considered to be one of the main causes of cardiovascular disease; therefore, further studies on different antipsychotics are needed to obtain additional results from a larger sample of patients with SCZ. Finally, our study did not assess confounding factors, such as age, diet, psychological stress, and lifestyle, which may affect the immune system and inflammatory response.

In summary, our results showed that patients with first-episode SCZ have pro-inflammatory and vascular inflammatory responses, reflecting low-grade inflammation. Tie-2 and IL-1β may be important mediators between inflammation and vascular dysfunction in patients with SCZ and may also be one of the predictors of increased cardiovascular disease in this population. Future prospective longitudinal studies should explore the role of Tie-2 and inflammatory cytokines in the vascular inflammation process in SCZ. Interventions aimed at reducing inflammation and vascular risk may help to reduce vascular endothelial dysfunction and, in turn, prevent cardiovascular morbidity and mortality in SCZ.