The Interrelationships between Cytokines and Schizophrenia: A Systematic Review
Abstract
:1. Introduction
2. Methods
- Articles with an abstract available.
- Full text can be retrieved.
- Articles written in English.
- Species: human.
- Articles with incomplete or unavailable full text.
- Exclude non-English articles.
- Articles that lack significant relevance to this review.
- Exclude non-human studies.
3. Results
3.1. Pro-Inflammatory Cytokines and Schizophrenia
3.1.1. IL-8
3.1.2. IL-6
3.1.3. IL-1β
3.1.4. TNF-α
3.1.5. IL-17
3.1.6. IL-12
3.1.7. IFN-γ
3.1.8. IL-2
3.1.9. IL-23
3.1.10. Chemokines
3.2. Anti-Inflammatory Cytokines and Schizophrenia
3.3. Other Cytokines and Schizophrenia
3.4. Anti-Inflammatory Treatment
3.5. The CKs in EVs and SCZ
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
SCZ | Schizophrenia |
CNS | Central nervous system |
CSF | Cerebrospinal fluid |
CKs | Cytokines |
EVs | Extracellular vesicles |
INF | Interferon |
TNF | Tumor necrosis factor |
FEP | First episode of psychosis |
IL | Interleukin |
TGF | Transforming growth factor |
MIP | Macrophage inflammatory protein |
NMDAR | N-methyl-D-aspartate receptor |
DAR | Dopamine receptor |
CRP | C-reactive protein |
sIL-2R | Interleukin-2 receptor |
HCs | Healthy controls |
CCL11 | Categorization protein-11 |
MCP-1 | Monocyte chemoattractant protein-1 |
MIP-1β | Macrophage inflammatory protein-1β |
TARC | Thymus- and activation-regulated chemokine |
MDC | Macrophage-derived chemokine |
BDNF | Brain-derived neurotrophic factor |
PEA | Palmitoyl ethanol amide |
MSC-exo | MSC-derived exosomes |
BBB | Brain–blood barrier |
MSC | Mesenchymal stem cell |
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Authors, Year and Country | Tissue | Upregulated | Downregulated | Main Finding | Reference(s) |
---|---|---|---|---|---|
Potvin, S. et al., 2008, Canada | Serum plasma | sIL-2R, IL-1RA, and IL-6 | IL-2 | It provides evidence for the hypothesis of SCZ inflammatory syndrome. | [34] |
Söderlund, J. et al., 2009, Sweden | CSF | IL-1β | This study provides evidence to support the activation of the brain’s immune system during the FEP. | [42] | |
Miller, B. J. et al., 2011, USA | Blood and CSF | IL-12, IL-6, IL-8, IFN-γ, TGF-β, IL-1RA, and TNF-α | The findings indicate that alterations in CK levels in SCZ may exhibit variability based on clinical status. | [40] | |
Dimitrov, D. H. et al., 2013, USA | Serum | GRO, MCP-1, MDC, and sCD40L | IFN-γ IL-2 IL-17 | The levels of CKs in individuals with SCZ demonstrated a positive correlation with both positive symptoms and PANSS. Pathway analysis revealed the involvement of these CKs in the IL17 pathway, suggesting a potential role for this pathway in the progression of SCZ. | [46] |
Di Nicola, M. et al., 2013, UK | Serum | IL-6, IL-1β, IL-8, and TNF-α | A history of childhood trauma was found to be related to elevated levels of serum TNF-α, while stressful life events were linked to increased expression of TNF-α mRNA in white blood cells. In summary, individuals experiencing their first episode of psychosis exhibit a pro-inflammatory state. | [29] | |
Leukocyte | IL-6 and TNF-α | ||||
Upthegrove, R. et al., 2014, UK | Plasma or serum | TNF-α, IL-1β, and IL-6 | It was found that the serum pro-inflammatory CK levels in patients with FEP increased significantly after drug treatment. This provides evidence for pro-inflammatory immune signs in SCZ. | [15] | |
Al-Hakeim, H. K. et al., 2015, Iraq | Serum | IL-6, IL-18, and TNFα | The study concluded that the immune response was significantly stimulated in the SCZ group. Due to the presence of heightened pro-inflammatory CKs, SCZ may be considered an inflammatory disease. | [35] | |
Petrikis, P. et al., 2015, Greece | Serum | IL-2 and IL-6 | IL-6- and IL-2-mediated inflammatory responses may contribute to the pathogenesis of SCZ. | [36] | |
Lv, M. H. et al., 2015, China | Serum | TNF-α | The PANSS exhibited a notable association with TNF-α, suggesting a potential association between immune dysregulation and the manifestation of psychopathological symptoms in individuals with SCZ, as well as cognitive impairment. | [43] | |
El Kissi, Y. et al., 2015, Tunisia | Serum | IL-17 | SANS was negatively correlated with IL-17 and positively correlated with IFN-γ. This study suggests that IL-17 may be a valuable biomarker for SCZ. | [47] | |
Borovcanin, M. et al., 2015, Serbia | Serum | IL-23 | Elevated IL-23 levels in patients with psychosis, irrespective of antipsychotic treatment, appear to serve as an inherent biomarker for the disease. | [50] | |
Goldsmith, D. R. et al., 2016, USA | Blood | IL-1RA, TNF-α, sIL-2R, and IL-6 | The treatment of the disease leads to a reduction in pro-inflammatory CKs and elevated anti-inflammatory CKs. | [41] | |
Li, H. et al., 2016, China | Plasma | IL-17, IL-23, and TGF-β1 | IL-17 level was positively correlated with SCZ severity and aggressive behavior. Research suggested that elevated IL-17 levels may serve as a potential biomarker for both SCZ and aggressive behavior. | [49] | |
Hong, S. et al., 2017, USA | Plasma | MCP-1, MIP-1β, CCL11, TARC, and MDC | The linear combination of CCL11 and MDC exhibited a positive correlation with age, severity of negative symptoms, and duration of SCZ. With advancing age, interventions targeting the normalization of chemokine levels may potentially enhance the physical and mental well-being of individuals with SCZ. | [51] | |
Lesh, T. A. et al., 2018, USA | Plasma | IL -1β, IL-2, IL-6, and IFN-γ | The percentage of grey matter in the whole brain was negatively correlated with levels of IL-12 and IFN-γ, while the thickness of the prefrontal cortex showed a positive correlation with IL-12 and IFN-γ. Additionally, the IL-1β level was positively associated with psychotic symptoms in SCZ. | [37] | |
Dahan, S. et al., 2018, Israel | Serum | IL-8, IL-2R, and IL-6 | The PANSS score exhibited a positive correlation with the levels of IL-6 and IL-2R. | [27] | |
Gallego, J.A. et al., 2018, USA | CSF | IL-1β, IL-6, and IL-8, | Subgroup analyses of IL-6 revealed that antipsychotics had no significant effect on IL-6 levels but were associated with increased IL-6 values in the early stages of the disease. | [28] | |
Xu, L. et al., 2018, China | Peripheral blood mononuclear cells | IL-8 | The involvement of IL-8 in the pathophysiological changes observed in SCZ appears to be specific. Furthermore, these findings offer novel evidence supporting the autoimmune hypothesis of SCZ. | [31] | |
Quidé, Y. et al., 2019, Australia | Serum | IL-6 and TNF-α | The distinct association between exposure to trauma and levels of pro-inflammatory CKs across various diagnostic categories implies that trauma may exert diverse effects on stress and the immune system within these patient populations. | [38] | |
Ermakov, E.A. et al., 2023, Russia | CSF | IL-8 | Dysregulation of chemokine expression may contribute to the development of neuroinflammation in individuals with SCZ. | [32] | |
Blood | IL-8, MIP-1β, MCP-1, and CCL11 | ||||
Halstead, S. et al., 2023, Australia | IL-2, IL-1β, IL-8, TNF-α, IFN-γ, and IL-6 | IL-12 | Individuals with SCZ spectrum disorder have baseline levels of altered inflammatory proteins throughout the course of the disease, which are reflected in persistently elevated pro-inflammatory proteins, while patients with acute psychosis may have superimposed immune activity. | [33] | |
Patlola, S. R. et al., 2023, Ireland | Plasma | IL-1β, IL-6, and TNF-α | Among patients with SCZ, a significant inverse correlation was observed between cognitive performance in five domains (executive function, attention processing speed, verbal and visual learning and memory, working memory) and systemic plasma levels of TNF-α, IL-1β, and IL-6. | [39] |
Author, Year and Country | Tissue | Upregulated | Downregulated | Main Finding | Reference(s) |
---|---|---|---|---|---|
Potvin, S., 2008, Canada | Peripheral blood leukocytes | IL-1RA | IL-1RA is produced primarily by innate immune cells, indicating primary alterations in the SCZ immune system. | [34] | |
Kunz, M., 2011, Brazil | Serum | IL-10 | The results showed chronic immune activation of SCZ. | [52] | |
Xiu, M.H., 2014, China | Serum | IL-10 | Decreased IL-10 may be linked to negative symptoms of SCZ and cognitive impairment. | [53] | |
Li, H., 2016, China | Plasma | TGF-β1 | TGF-β1 levels were positively correlated with PANSS. | [49] | |
Goldsmith, D.R., 2016, USA | Blood | IL-1Ra | The heterogeneity of IL-1RA was not significant. | [41] | |
Fu, G., 2019, China | Venous blood | IL-10 | Elevated levels of IL-10 are associated with a breakdown of the integrity of the microstructure of white matter in SCZ. This evidence suggests that inflammation can regulate the pathological microstructure of white matter and is closely associated with SCZ. | [54] | |
Zhou, Y., 2019; China | Plasma | IL-1Ra | IL-1Ra may play an important role in the etiology of SCZ. | [44] | |
Mednova, I.A., 2022, Russia | Serum | IL-10 | In a SCZ course of 10 years or more, IL-10 levels were higher than those in a SCZ course of 5 years or less. CK imbalances in individuals with SCZ are revealed, depending on the gender and clinical features of the disease. | [55] | |
Halstead, S., 2023, Australia | — | IL-10 and IL-1Ra | IL-4 | Study quality and methodological, demographic, and diagnostic factors for most of the assessments did not significantly affect the results for most inflammatory markers. | [33] |
Author, Year and Country | Tissue | Upregulated | Downregulated | Main Finding | Reference(s) |
---|---|---|---|---|---|
Bresee, C., 2009, USA | Serum | sIL-2R | Elevated SIL-2R levels are associated with etiology. | [56] | |
Fernandez-Egea, E., 2013, UK | Plasma | CCL11 | CCL11 may be involved in the harmful effects of cannabis on brain function and mental health disorders. | [60] | |
Xiu, M.H., 2015. China | Serum | IL-3 | There was a positive correlation between IL-3 level and PANSS. The findings suggested that the IL-3 pathway is related to the etiology of SCZ. | [57] | |
Fu, Y.Y., 2016, China | Serum | IL-3 | Reduced IL-3 levels in SCZ suggest that immunosuppression may be associated with the development of SCZ. | [58] | |
Chase, K.A., 2016, USA | Peripheral lymphocytes | CBRs mediate cytokine release, with dysregulated CK levels demonstrated in individuals with SCZ. | [61] |
Antipsychotics. | Effects | Cytokines | References |
---|---|---|---|
Fingolimod | Neuroprotective and anti-inflammatory | — | [67] |
Berberine | Improves negative symptoms through anti-inflammatory effects | CRP ↓ | [68] |
PEA and risperidone | Safe relief of primary negative symptoms | — | [69] |
Risperidone | Anti-inflammatory effect | TNF-α ↓, IL-6 ↓, IL-1β ↓, | [70] |
Adalimumab | Effective in the treatment of negative and general psychopathological symptoms without side effects | IL-8 ↓, CRP ↓, TNF-α ↓, IL-6 ↓, and IL-1β ↓ | [71] |
Minocycline | Anti-inflammatory and neuroprotective | TNF-α ↓, IL-1β ↓, and IL-6 ↓ | [72] |
Risperidone | Anti-inflammatory and neuroprotective | IL-6 ↓ and TNF-α ↓ | [72] |
Clozapine | Clozapine exhibited a more pronounced impact on immune function in female patients diagnosed with SCZ | IL-2 ↓ | [73] |
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Lv, H.; Guo, M.; Guo, C.; He, K. The Interrelationships between Cytokines and Schizophrenia: A Systematic Review. Int. J. Mol. Sci. 2024, 25, 8477. https://doi.org/10.3390/ijms25158477
Lv H, Guo M, Guo C, He K. The Interrelationships between Cytokines and Schizophrenia: A Systematic Review. International Journal of Molecular Sciences. 2024; 25(15):8477. https://doi.org/10.3390/ijms25158477
Chicago/Turabian StyleLv, Haibing, Meng Guo, Chuang Guo, and Kuanjun He. 2024. "The Interrelationships between Cytokines and Schizophrenia: A Systematic Review" International Journal of Molecular Sciences 25, no. 15: 8477. https://doi.org/10.3390/ijms25158477