The role of TLR-2, TLR-4, and the NF-κB pathway in increased cardiovascular risk in patients with schizophrenia

Backgraund: Schizophrenia is a chronic psychiatric disorder characterised by positive and negative symptoms and cognitive impairment. With a prevalence of approximately 1% in the general population, this disease shortens life expectancy by 10-25 years compared to the general population, and cardiovascular diseases are among the main causes of early mortality. This increased risk is associated with genetic predisposition, lifestyle factors, side effects of antipsychotic drugs and especially immune system dysregulation. Current research emphasises that the immune system plays an important role in the relationship between schizophrenia and cardiovascular diseases. In this context, Toll-like receptors (TLR-2 and TLR-4) and nuclear factor kappa-B (NF-κB) signalling pathway are suggested to play a central role in inflammatory processes. The aim of this study was to evaluate the relationship between increased cardiovascular risk in schizophrenia and TLR-2, TLR-4 and NF-κB signalling pathways. Method: This cross-sectional study was conducted to investigate the relationship between increased cardiovascular risk and TLR-2, TLR-4 and NF-κB signalling pathways in individuals with schizophrenia. The study included 77 schizophrenia patients diagnosed according to DSM-5 diagnostic criteria, who were in remission for the last 6 months and had PANSS scores <70, and 50 age- and sex-matched healthy controls. Peripheral blood samples were collected from the participants and immunological parameters were evaluated by flow cytometry and ELISA methods, while cardiovascular evaluations were performed using flow-induced dilation (FMD), global longitudinal strain (GLS), carotid intima-media thickness (IMT), mitral valve E/A and E/E ratios and left ventricular ejection fraction (LVEF) measurements. Hierarchical logistic regression and multivariate analysis of covariance (MANCOVA) methods were used to analyse the data. Result: The study included 77 schizophrenia patients and 50 healthy controls. In the schizophrenia group, BMI, waist circumference, TG levels, QRISK3 score, carotid IMC and diastolic dysfunction parameters were significantly higher, while GLS and mitral valve E/A ratios were significantly lower. Among the inflammatory parameters, IL-6 and IL-10 levels were significantly higher in the schizophrenia group, while IFN-γ and NF-κB levels were significantly lower. In flow cytometric analysis, classical monocyte ratio, TLR-2 and TLR-4 expression (especially in classical and intermediate monocytes) and HLA-DR intermediated monocyte MFI levels were significantly higher in schizophrenia patients, while nonclassical monocyte ratio and TLR-4 nonclassical monocyte MFI levels were significantly lower. Regression analysis showed that IL-6 and NF-κB levels strongly predicted schizophrenia diagnosis. Conclusion: This study evaluated immunological and inflammatory mechanisms associated with increased cardiovascular risk in schizophrenia. Our findings suggest that increased IL-6 and IL-10 and decreased IFN-γ and NF-κB in individuals with schizophrenia may reflect disease-related inflammatory processes. Subtype-specific differences in TLR-2 and TLR-4 expression and HLA-DR expression in monocyte subgroups support the role of immune system dysregulation in the pathogenesis of schizophrenia. In addition, a significant increase in cardiovascular parameters such as QRISK3 score, triglyceride levels and carotid intima-media thickness, and a significant decrease in GLS and mitral valve E/A ratio were observed in the schizophrenia group. These findings emphasise the clinical importance of cardiovascular risk assessment of schizophrenia patients in combination with inflammatory and immune parameters. Future studies should elucidate the prognostic and therapeutic potential of these parameters.