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Alterations in innate immunity may underlie the pathophysiology of schizophrenia (SZ). Toll-like receptor-4 (TLR4) is a master element of innate immunity. The specificity proteins (SPs), transcription factors recently implicated in SZ, are putative regulatory agents of this. This work was aimed at describing alterations in the TLR4 signalling pathway in postmortem brain prefrontal cortex (PFC) and cerebellum (CB) of 16 chronic SZ patients and 14 controls. The possible association of TLR4 pathway with SP1 and SP4 and SZ negative symptomatology is explored. In PFC, TLR4/myeloid differentiation factor 88 (MyD88)/inhibitory subunit of nuclear factor kappa B alpha (IκBα) protein levels were lower in SZ patients, while nuclear transcription factor-κB (NFκB) activity, cyclooxygenase-2 (COX-2) expression and the lipid peroxidation index malondialdehyde (MDA) appeared increased. The pattern of changes in CB is opposite, except for COX-2 expression that remained augmented and MDA levels unaltered. Network interaction analysis showed that TLR4/MyD88/IκBα/NFκB/COX-2 pathway was coupled in PFC and uncoupled in CB. SP4 co-expressed with TLR4 and NFκB in PFC and both SP1 and SP4 co-expressed with NFκB in CB. In PFC, correlation analysis found an inverse relationship between NFκB and negative symptoms. In summary, we found brain region-specific alterations in the TLR4 signalling pathway in chronic SZ, in which SP transcription factors could participate at different levels. Further studies are required to elucidate the regulatory mechanisms of innate immunity in SZ and its relationship with symptoms.

Original publication

DOI

10.1016/j.pnpbp.2017.08.005

Type

Journal article

Journal

Prog neuropsychopharmacol biol psychiatry

Publication Date

03/10/2017

Volume

79

Pages

481 - 492

Keywords

Innate immunity, Negative symptoms, Network interaction analysis, Oxidative/nitrosative stress, Transcription factors, Aged, Cerebellum, Chronic Disease, Cyclooxygenase 2, Gene Expression Regulation, Humans, Male, Myeloid Differentiation Factor 88, NF-KappaB Inhibitor alpha, NF-kappa B, Prefrontal Cortex, Psychiatric Status Rating Scales, Schizophrenia, Schizophrenic Psychology, Signal Transduction, Toll-Like Receptor 4