This study identified a novel cytokine profile, IRS/CIRS, to be significantly higher in the FEPS group and its negative association with whole-brain white matter average FA. Among the white matter microstructures, only CST showed significant correlation with IRS/CIRS in FEPS. These findings suggest that IRS/CIRS could be a novel biomarker for exploring the role of immune imbalance in the pathophysiological mechanism of schizophrenia.
Our first hypothesis that plasma IRS/CIRS is significantly higher in FEPS than in HCs was strongly supported by previous studies[5, 6, 13, 15, 17]. Maes et al. had shown the expression level of IRS/CIRS to be significantly elevated in antipsychotic naïve first-episode psychosis, with activation of the IRS and CIRS response[15, 17]. Compared with CIRS, the IRS response was relatively greater for IL6, IFNγ, and TNFα levels in the serum samples. Our findings were in line with those of Maes et al.; however, we incorporated another proinflammatory cytokine, IL1β, in the IRS profile. The present results were consistent with a previous report that IL1β is elevated in first-episode psychosis. This cytokine decreased following treatment and was exacerbated with acute relapse of chronic schizophrenia, indicating that IL1β is closely correlated with changes occurring in schizophrenia. It was reported that IL1β could stimulate the production of kynurenic acid which was associated with schizophrenia symptoms and cognitive dysfunction. Additionally, IL1β can make for aberrant release and accumulation of glutamate, which reportedly results in the death of neurons and oligodendrocytes. Therefore, we believe that it is necessary to include IL1β in IRS profile along with IL6, IFNγ, and TNFα.
Table 2 demonstrates that contrary to the significantly high IRS in FEPS, CIRS showed only a slight upward trend. Therefore, it is obvious that compensatory mechanisms were insufficient. IL4 was decreased in FEPS, consistent with the meta-analysis results. IL4 may act as an immune regulator and is a major player in CIRS. IL4 activates M2 macrophages to promote the production of IL10 and TGFβ and suppresses the production of IL1β, IL6, and TNFα. Additionally, the release of IL1Ra is enhanced by IL10. These cytokines are all present in the CIRS profile and attenuate the proinflammatory function. For example, proinflammatory cytokines could reduce the production of BDNF mRNA in astrocytes and IL4 could reverse this effect and directly induce astrocytes to produce BDNF mRNA. The decreasing expression of IL4 may result in severe cognitive impairment.
Most cytokines and the three cytokine profiles analyzed were highly associated with each other (p < 0.01; Supplementary Fig. S1). These results were consistent with those of Chutima et al. and indicate generalized immune activation. It is reasonable to believe that computing profiles of cytokines would perform better than single inflammatory markers to explore the effects of immune abnormalities on schizophrenia. The present results of Cohen’s d also showed that among all the included cytokines and the three types of cytokine profiles, the largest effect size of the difference between the FEPS and HCs groups was for IRS/CIRS (d = 0.74).
Additionally, we had hypothesized that a higher IRS/CIRS was negatively associated with whole-brain white matter average FA in FEPS, unlike HCs. The results of our study showed that the integrity of the white matter measured by FA was significantly lower in the FEPS compared with the HCs. In schizophrenia, cognitive function was impaired in all domains measured by the MATRICS Consensus Cognitive Battery, which may indicate widespread reduction in the integrity of whole brain white matter. This consistent with other research results that the combined function of pro- and anti- inflammatory factors could result in the decreased integrity of the white matter fiber tracts, attributable to pathological changes in myelin and neurofilament. Through regulating oligodendrocyte, the most important myelinating cell, cytokines play a vital role in moderating inflammation that alters white matter development. The specific function of cytokines in oligodendrocytes and neurons could explain this.
TNFα targets the TNF receptor expressed by oligodendrocyte progenitors and exerts an inhibitory role in the survival and differentiation of this cell type. Furthermore, TNFα can hinder the development of oligodendrocytes and the expression of myelin basic protein mRNA, which can maintain the stability of myelin structure and function. IL-1β impedes oligodendrocyte progenitor cell (OPC) recruitment by targeting IL-1R1 to inhibit white matter restoration and functional renewal. Elevated IL-6 levels induce demyelination and are correlated with neurofilament damage. IL4 plays an indispensable role in facilitating white matter integrity and repairing injured white matter. It acts directly on peroxisome proliferator-activated receptor gamma to promote OPC into mature oligodendrocytes that produce myelin. Although previous studies found that elevated peripheral IL10 was associated with reduced white matter FA, we believe that it is the compensatory mechanism of CIRS in response to IRS, which is the initial factor related to the decrease in FA. Inflammation suppression, IL10, and TGF-β have been reported to promote re-myelination and neuron/axonal growth by mediating the expression of growth arrest–specific gene 6 as a therapeutic intervention for demyelination and glial cell development.
The IRS profile cytokines, IL1β, IL6, IFNγ, and TNFα, transferred from the periphery or secreted from chronically activated microglia, could exert deleterious effects on oligodendrocytes and neurons by stimulating kinases and caspase cascades, leading to cell death[20, 36]. CIRS profiles, including IL4, IL10, and TGF-β, could promote healing and limit neuronal injury. The IRS/CIRS ratio reflects the general effects of cytokines on oligodendrocytes and neurons.
CST was significantly associated with IRS/CIRS, suggesting that some white matter tracts may be more assailable to proinflammatory cytokines in FEPS. A Chinese study demonstrated the association of decreased FA in the CST with voluntary motor function in patients with severe negative symptoms. Moreover, low FA in the CST exists in patients with treatment-resistant schizophrenia and explains their poor performance in complex motor tasks. Combined with the findings of our study, it may be suggested the effects of IRS/CIRS on motor deficits may have already occurred during schizophrenia onset.
Although we did not find the correlation between PANSS scores and IRS/CIRS in FEPS, it is promising to find an association in chronic schizophrenia, as IRS/CIRS imbalance also exists in chronic psychosis and illness duration may promote the influence of cytokines on white matter integrity. In chronic disease, the corpus callosum is vulnerable to inflammatory markers[6, 21]. We intend to explore the relationship of IRS/CIRS and white matter in chronic disease and its difference with FEPS in our future research.
Our study has some limitations. First, this was a cross-sectional study, and the effects of IRS/CIRS on white matter integrity were not examined. Further studies in patients with chronic schizophrenia are needed. Second, the number of participants who completed all experiments, especially for acquiring valid imaging data, was small. This may have resulted in some promising associations being missed, such as genu of corpus callosum with IRS/CIRS. Third, the high sensitivity and specificity of the multi-cytokine detection ELISA kit, which aided in acquiring raw expression data in a short time, could have resulted in decreased variation coefficients.
In conclusion, our findings suggest that IRS/CIRS was significantly higher in FEPS and was negatively correlated with whole-brain white matter average FA. This indicates that IRS/CIRS is a novel biomarker for exploring the role of immune imbalance in the pathophysiological mechanism of schizophrenia.