Expression and Functionality Study of 9 Toll-Like Receptors in 33 Drug-Naïve Non-Affective First Episode Psychosis Individuals: A 3-Month Study

Abstract

Toll-like receptors (TLRs) are a pivotal component of the innate immune system that seem to have a role in the pathogenesis of psychosis. The purpose of this work was to compare the expression and functionality of 9 TLRs in three peripheral blood mononuclear cells (PBMCs) (monocytes, B cells, and T cells) between 33 drug-naïve first-episode psychosis (FEP) individuals and 26 healthy volunteers, at baseline and after 3-month of antipsychotic treatment. The expression of TLRs 1–9 were assessed by flow cytometry. For the assessment of the TLR functionality, cells collected in sodium heparin tubes were polyclonally stimulated for 18 h, with different agonists for human TLR1–9. The results of our study highlight the role that TLR5 and TLR8 might play in the pathophysiology of psychosis. We found a lower expression of these receptors in FEP individuals, regarding healthy volunteers at baseline and after 3-month of treatment on the three PBMCs subsets. Most TLRs showed a lower functionality (especially reduced intracellular levels of TNF-α) in patients than in healthy volunteers. These results, together with previous evidence, suggest that individuals with psychosis might show a pattern of TLR expression that differs from that of healthy volunteers, which could vary according to the intensity of immune/inflammatory response.

Immune System Abnormalities in Schizophrenia: An Integrative View and Translational Perspectives

“…There is evidence that TLR1, TLR2, TLR4, TLR6, and TLR9 expression levels in peripheral blood mononuclear cells (PBMCs) are reduced in schizophrenia, TLR3 and TLR7 levels are elevated, and TLR5 and TLR8 levels do not differ from controls ( 24 ). In another study, TLR5 and TLR8 expression levels in PBMCs decreased in drug-naïve first-episode psychosis individuals before and after treatment compared to controls ( 25 ). A lower functional activity of TLRs after agonist activation has also been shown.…”

The role of Toll‐like receptors in neuropsychiatric disorders: Immunopathology, treatment, and management

“…TLRs often presented a reduced functionality (in particular decreased intracellular concentrations of TNF‐α) in patients compared to healthy subjects. Together, these findings indicate that individuals with psychosis could present with a pattern of TLR production that is distinct from that of healthy subjects, that could fluctuate based on the severity of immunological feedback 272 …”

“…270 A study compared the production that is distinct from that of healthy subjects, that could fluctuate based on the severity of immunological feedback. 272…”

Counting the Toll of Inflammation on Schizophrenia—A Potential Role for Toll-like Receptors

“…[ 60 ]. Multiple studies show altered protein and mRNA expression of TLRs in schizophrenia ( Table 1 ) compared to healthy adults [ 61 , 62 , 63 ]. Human postmortem studies carried out on individuals diagnosed with schizophrenia, brain samples showed lower tlr4 mRNA and protein levels, and downregulation of il6 , il10 , and tnfa mRNA in the prefrontal cortex (PFC) region [ 64 , 65 ], and elevated TLR4 protein levels in the cerebellum region [ 64 ].…”

“…In contrast, whole blood stimulation studies in schizophrenia showed elevated concentrations of IL-6, TNF-α, and IL-1β post-TLR2 stimulation, and increased IL-1β alone post-TLR4 and 8 stimulation [ 7 ]. Individual blood cell studies in FEP patients showed lower TLR protein expression in monocytes, B cells, and T cells [ 63 ]. Overall, we can infer that dysregulation of TLR expression exists in patients with schizophrenia and varies at various stages of disease progression, but we do not have sufficient evidence to implicate their extent of involvement in the immunopathology of schizophrenia.…”