Psychiatric disorders, such as schizophrenia and major depressive disorder (MDD), result from complex interactions between genetic and environmental factors that lead to developmental or neurological impairment (1, 2). The overlapping clinical phenotypes and genetic associations observed with various psychiatric disorders suggest a potential for shared elements of their disease etiology (3–6).

Considerable evidence indicates that disruption of the immune system due to inflammation has a critical role in psychiatric disorders, including schizophrenia and depression (3, 4, 7). Recent data indicate the presence of typical inflammation responses in schizophrenia and depression (3, 8–10). Epidemiological studies have revealed that the presence of an autoimmune disease is a high-risk factor for psychiatric disorders (11, 12). A series of genome-wide association studies (GWAS) of schizophrenia confirmed that the immune system is involved in the pathogenesis of schizophrenia and depression, including the HLA gene (a complement gene) and the interleukin gene family (13–15). Furthermore, overactivation of microglia in the brain and changes in lymphocyte functions in the systemic circulation also have been reported in previous studies (3, 16). Increases in pro-inflammatory factors (e.g., IL-1, IL-6, and TNF-α) or reduction of anti-inflammatory factors (e.g., IL-4 and IL-10) also were found in the serum of patients with mental disorders (17–19). In addition, animals with overactive inflammatory cytokines displayed schizophrenia- or depressive-like behaviors, and the cytokines induced neuronal loss and synaptic impairment (20, 21), which are common characteristics observed in schizophrenia and depression.

Although the relationship between the immune system and psychiatric diseases has been studied extensively, the underlying mechanisms of action are still unclear. The functions of immune molecules in vivo are complex and overlap to orchestrate complex behaviors (22, 23). Essential questions still need to be answered, including, are there additional critical immune molecules that have significant roles in schizophrenia and depression? Also, are there differences among immune molecules that mediate functions between schizophrenia and depression?

Our previous data indicated that the receptor subunit of IL-15, IL-15Rα, is an important immune molecule that maintains normal nervous system functions. We reported that IL15Rα knockout (KO) mice displayed hyperactivity in the open-field test, reduced social interactions in the three-chamber test, defects in learning ability in the T-maze, and depressive-like behavior in the forced immobility test (24–26). Collectively, these results indicate that IL-15Rα plays an important role in schizophrenia and depression. Furthermore, we found a rare mutation in the IL-15RA gene that impeded IL-15Rα intracellular signal transduction in schizophrenia patients (27). As the ligand of IL-15Rα, IL-15 is a cytokine especially poised to have a pivotal role in CNS organization, and it also has been reported to be a biomarker of schizophrenia and depression (28–30). In fact, IL-15RA mRNA is widely expressed in the brain, including in microglia, astrocytes, and neurons, and it exhibits a major signaling role in regulating brain homeostasis and development (31–33). For example, IL-15/IL-15R could reduce the serotonin transmission which led to the depressive phenotypes in mice (25). Previous study also demonstrated that IL-15/IL-15R resisted environment stress through Akt signaling transmission (34). IL-15Rα is ubiquitously produced in the brain as well as other organs; it activates multiple intracellular kinases through a trimeric receptor complex consisting of its specific receptor IL-15Rα and co-receptors interleukin 2 receptor β and interleukin 2 receptor γ (32, 35, 36). Both IL-15 and IL-15Rα have multiple splice variants and exist in different subcellular compartments (37–40), suggesting that IL-15 signaling exhibits vital functions in neurodevelopment. IL-15 also can signal through IL-15Rα in the absence of other members of the trimeric complex, suggesting that this particular monomeric signaling unit has specific functions (41). We have observed that IL-15Rα KO mice display defects in GABAergic and serotonergic transmission, contributing to the phenotypes of schizophrenia and depression (24–26). The deficits observed in IL-15Rα KO mice are greater than those seen in mice without interleukin 2 receptor β (42), brain-derived interleukin 2 (43), or interleukin 2 receptor γ co-receptor (42, 44).

In this study, we investigated whether IL-15Rα was associated with the risk for psychiatric disorders by comparing the serum-soluble IL-15Rα levels in patients with schizophrenia or depression and healthy controls. We also explored the association of IL-15Rα expression with psychiatric symptoms in patients. We observed whether similar psychiatric symptoms were shown in mice with depletion of IL-15Rα. When combined with our previous results from animal experiments, this study provided clinical evidence of the role of IL-15Rα in psychiatric diseases.

The present study investigated potential connections between IL-15Rα levels in serum and the risk of schizophrenia and depression. Three findings were obtained in our study. (1) Patients with schizophrenia but not depression showed significant reductions in serum IL-15Rα levels compared to healthy controls. (2) A significant negative correlation was found between serum IL-15Rα concentrations and the excited component of the PANSS scores in schizophrenia patients. (3) A remarkable terrified response in the IL-15Rα KO mice was observed in the PPI test, and the KO mice displayed obvious PPI impairment.

Several published reports have confirmed that IL-15Rα insufficiency results in multiple disorders, including but not limited to immunodeficiency, skeletal muscle variations, and a range of neurological symptoms (24, 50–54). The presence of inflammation is an essential etiological hypothesis in psychiatric diseases, including schizophrenia and depression, and we observed alterations in the serum levels of IL-15Rα in patients with schizophrenia and depression in this study. Interestingly, we found a significant reduction in IL-15Rα levels in schizophrenia but no changes in depressive patients. Notably, we also found a distinct decrease of IL-15Rα in schizophrenia patients compared to depressive patients. These observations correlated with our previous study that showed variants of the IL-15RA gene are associated with schizophrenia using IL-15RA exon sequencing (27).

Several reasons might be related to the different expression of IL-15Rα in serum between schizophrenia patients and depressive patients. First, although clustering analysis showed that schizophrenia and MDD share similar patterns of inflammatory changes, genome-wide genetic studies (7) have reported evidence that supports the presence of a more extensive inflammatory response in schizophrenia than depression. For example, patients with schizophrenia exhibited higher levels of inflammatory markers in their circulatory system than depressive patients or healthy controls (55). A recent postmortem study using transcriptional profiling revealed that samples from schizophrenia patients showed increased expression of transcripts associated with inflammation across all brain regions examined (3). These findings were not evident in patients with bipolar disease or depression or rat brains following chronic dosing with antipsychotic drugs (3). Second, in addition to exhibiting altered inflammatory responses, IL-15Rα KO mice exhibit several unique alterations in brain development and function without increased mortality (31, 32). IL-15Rα also was involved in blood-brain barrier development, affecting cellular permeability (56). Based on the Developing Human Transcriptome database¹, we observed that IL-15Rα is not expressed in the brain before birth but rises sharply after birth, reaching a peak at the age of 2 and 3, and then high levels of expression are maintained. These data suggested that the function of IL-15Rα is essential during early postnatal brain development. Considering the close relationship between impairment of brain development and schizophrenia, we speculated that a greater reduction in IL-15Rα might accompany schizophrenia. Third, most of the patients were taking antipsychotics (68% in schizophrenia and 72% in depression), so the influence of antipsychotics on IL-15Rα levels should be considered. Although no study so far illustrated the effect of antipsychotics on IL-15Rα, several data showed the significant changes in circulating IL-15 levels in schizophrenia patients than that in controls, yet no significant change of IL-15 levels were found in patients prior and pose-treated with 6-8 weeks of antipsychotics (29, 57). Moreover, there was no remarkable difference in IL-15Rα levels in schizophrenia patients treated with or without antipsychotics before enrollment (Supplementary Table 1). Our covariance analysis controlling for antipsychotics also found a significant decrease in schizophrenia patients while not in patients with depression. These suggested that antipsychotics might have limited effect on circulating IL-15Rα levels.

The underlying reason for reduced soluble IL-15Rα in the plasma of schizophrenia patients was elusive. It was plausible that the decrease in the membrane protein IL-15Rα, the source of soluble receptors, contributed to the reduction in soluble IL-15Rα. Another reason might be a decrease in cleaved enzyme activity, which removes the soluble IL-15Rα from the membrane protein IL-15Rα, such as TACE/ADAM17 (58, 59). This possibility was supported by a previous study in which schizophrenia patients exhibited significantly higher levels of ADAM17 mRNA in whole blood compared to controls (60). However, another postmortem study by Marballi et al., demonstrated that ADAM17 protein levels in schizophrenia patients were significantly higher than controls in BA9 (61). These data suggested that different alterations in IL-15Rα levels might be found between the peripheral systems and brain, especially with respect to the subregions of the brain.

We analyzed the association of IL-15Rα levels and clinical symptoms in the schizophrenia patients further to assess the relationship between IL-15Rα and schizophrenia phenotypes. We found that serum IL-15Rα levels showed a considerable, negative correlation with the excited phenotype in schizophrenia patients. This result was verified by our animal study, which indicated that the IL-15Rα KO mice displayed a distinct PPI impairment, which was considered the endophenotype of schizophrenia. It was noteworthy that our previous data indicated that the IL-15Rα KO mice exhibited hyperactivity in the open-field test (54). The hyperexcitability induced by reduced IL-15Rα levels or deficiency could be mediated by synaptic redundancy or insufficient GABAergic transmission. Huang et al., demonstrated that IL-15 treatment of rat neural stem cells reduced neurite outgrowth in differentiating neurons, suggesting that insufficient IL-15Rα signaling might induce hyperexcitability in neurons through excessive neurites (62). Our previous work indicated that reduced expression of IL-15Rα resulted in the reduced expression of GABA in hippocampal homogenates, resulting in enhanced excitatory transmission in the nervous system (24). In addition, the IL-15Rα KO mice also displayed a higher startle reflex, which manifested as the increased startle amplitude than wild type in this study. The reduced GABA or glycine transmissions, or the increased glutamate transmission might contribute to excessive startle response, also suggesting that IL-15Rα was associated with increased excitability (63–66). These data promoted the viewpoint that the reduced IL-15Rα not only resulted in schizophrenia, but also contributed to the excitatory phenotype in schizophrenia.

Although few reports have described a role for IL-15Rα in schizophrenia, several studies have demonstrated that the underlying mechanism might be related to abnormal lipid and energy biosynthesis and metabolism. In fact, IL-15 has attracted considerable attention as a potential regulator to prevent and/or treat obesity and metabolic dysfunction (67). IL-15 might reduce triacylglycerol absorption and has been shown to inhibit lipid deposition in murine 3 T3-L1 preadipocytes (68). Moreover, an earlier study using fluorescence resonance energy transfer and confocal microscopy reported that IL-2 and IL15Rα were co-expressed in a supramolecular receptor cluster in lipid rafts of T cells, indicating that these molecules might have essential functions in lipid metabolism (69). The global IL-15Rα KO mice exhibited lower body fat levels, which provided direct evidence of a role of IL-15Rα in lipid regulation (54, 70, 71). Our recently published work with RNA-seq of the cortex and hippocampus of IL-15Rα KO mice identified three functional clusters, including respiratory chain and electron transport, regulation of steroid processes, and skeletal muscle development (72). These results highlight the important role of IL-15Rα in lipid and energy metabolism, which might be mediated through STAT3 phosphorylation (27, 62).

Several limitations should be noted in this study. First, the sample size of each group was small, especially the MDD group. The disequilibrium might affect the reliability of results. Second, the confounding effect of antipsychotics on the changes in serum IL-15Rα levels in patients could not be ruled out although we did not observe any effect of antipsychotic treatment on serum IL-15Rα levels in schizophrenia patients (Supplementary Table 1). Cohort studies of antipsychotics therapy are needed in the following study. In addition, the blood collection without fasting also might be a confounding factor on serum IL-15Rα levels. Third, the cognitive function was not evaluated in depressive patients in this study.

Therefore, although this was a pilot study, when the data were considered collectively, they revealed a definitive reduction in serum IL-15Rα levels in schizophrenia patients. Furthermore, such insufficiency or lack of IL-15Rα could induce hyperexcitability in the experimental mouse model and schizophrenia patients.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Independent Ethics Committee (IEC) of the Beijing Anding Hospital, Capital Medical University, Beijing, China (2015127FS-2). The patients/participants provided their written informed consent to participate in this study. The animal study was reviewed and approved by the Animal Use and Care Committee at Capital Medical University.

YH, ZS, and CW were responsible for study design. QB, ZM, and ML were responsible for recruiting the patients, performing the clinical rating, and collecting the samples. YH and ZS were responsible for the assay of IL-15Rα concentration in participants. YH and HW were responsible for the animal experiments. ZS, YH, JY, and CW were involved in the manuscript preparation and providing the funding for the study. AK and WP were involved in the manuscript revision. All authors have contributed to and have approved the final manuscript.

WP was employed by the company BioPotentials Consult. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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