Investigating the relationship between toll-like receptor activity, low-grade inflammation and cognitive deficits in schizophrenia patients – A mediation analysis

Background Schizophrenia is a debilitating psychiatric illness. Many studies report alterations in immune biomarkers (cytokines) in such patients. In addition, such prolonged low-grade inflammatory responses are associated with lowered cognitive performance. In this study, we investigated whether the expression and activity of Toll-like receptors (TLRs), receptors involved in initiating innate immune responses, are associated with the reported immune changes and, if so, whether they are associated with cognitive deficits in such patients. Methods 300 participants (202 healthy controls (HC) and 98 patients with schizophrenia (SZ)) were recruited. A battery of cognitive tasks using WAIS-III and CANTAB were administered to the participants. Whole blood collected from participants was used to assess TLR2, 3, and 4 activity. mRNA expression of cytokines and TLR1-10 were quantified using RT-QPCR. Using ELISA, plasma was analysed for basal levels of cytokines such as IL-6, IL-8, IL-10, IL-12, TNF-α, IFN-γ and C-reactive proteins (CRP). Results We found significantly elevated plasma levels of IL-6, IL-8, IL-10, TNF-α, and CRP in the SZ group. In the SZ patient-only group, significantly higher levels of TLR2 and −4 activity (as measured by IL-6, IL-8, and IL-10 release following agonist stimulation) were observed. Significant negative associations in patients were observed between plasma IL-6 levels and measures of attention & processing speed and working memory; IL-8 and intelligence quotient; TNF-α and logical memory; and social cognition and IL-10 and CRP. Multiple-linear regression analysis suggests that TLR2 and TLR4 activity was associated with increased and decreased cytokine levels respectively and decreased cognitive performance. Finally, the significant association between TLR activity and decreased cognitive performance was mediated by IL-6 and IL-8. Conclusion We have demonstrated that patients with schizophrenia have elevated protein and mRNA expression of a range of cytokines and Toll-like receptors. Some of these changes are associated with deficits in cognition. Finally, our study has demonstrated a modest relationship between TLR activity and cognitive deficits in schizophrenia patients in a manner that may be mediated by IL-6 and IL-8.