Abstract
Current pathophysiological models of schizophrenia focus on neurodevelopmental and immunological mechanisms. We investigated a molecular pathway traditionally linked to the neurodevelopmental hypothesis (neuregulin 1 - ErbB), and pathogen-associated pattern recognition receptors associated with the immune hypothesis (Toll-like receptors, TLRs). We recruited 42 first-episode, drug-naïve patients with schizophrenia and 42 matched healthy control subjects. In monocytes TLR4/TLR5 and ErbB expressions were measured with flow-cytometry. Pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and the anti-inflammatory cytokine IL-10 were determined following the stimulation of TLR4/TLR5 and ErbB. Results revealed increased TLR4/TLR5 and decreased ErbB4 expression in schizophrenia relative to the control subjects. The expression of ErbB2 and ErbB3 receptors was unaltered in schizophrenia. TLR4 stimulation resulted in lower pro-inflammatory cytokine production in schizophrenia compared to the control levels, whereas the stimulation of ErbB by neuregulin 1 led to higher pro-inflammatory cytokine levels in patients with schizophrenia relative to the control group. In healthy controls, ErbB activation was associated with a marked production of IL-10, which was dampened in schizophrenia. These results indicate that the stimulation of TLR4 and ErbB induces opposite pro-inflammatory cytokine responses in schizophrenia.
Highlights
Current pathophysiological models of schizophrenia focus on neurodevelopmental and immunological mechanisms
In addition to receptor expression, we investigated the production of proinflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10) cytokines by monocytes after stimulation with TLR4/TLR5 ligands (bacterial lipopolysaccharides (LPS) and flagellin, respectively) and neuregulin 1 (NRG1)
There was a significant difference between patients with schizophrenia and healthy control participants in the expression (mean fluorescent intensity (MFI) as measured by flow cytometry) of Toll-like receptor (TLR) and ErbB4: we observed an increased expression of TLR4 (F(1,82) = 30.21, p < 0.001; η2 = 0.27) and TLR5 (F(1,82) = 11.27, p < 0.005; η2 = 0.12) in patents with schizophrenia relative to the control subjects, whereas in the case of ErbB4, the opposite effect was found (F(1,82) = 31.30, p < 0.001; η2 = 0.28)
Summary
Current pathophysiological models of schizophrenia focus on neurodevelopmental and immunological mechanisms. New molecular genetic data, based on genome-wide association studies with better statistical power, suggest that major histocompatibility complex class I (MHC-I) molecules may form a bridge between genetic predisposition, immunological mechanisms, and environmental risk factors (e.g., maternal infection, obstetric complication, and stress) by regulating neurite growth, synapse formation, and activity-dependent synaptic tuning in the brain[13]. A timely and detailed review and a meta-analysis by Mostaid et al.[16,22] demonstrated that, despite the fact that whole-genome association studies did not confirm a link between NRG1/ErbB genes and schizophrenia, there is substantial evidence from other types of preclinical and clinical studies that NRG1 may be relevant in the pathophysiology of schizophrenia by regulating synapse formation but the balance between excitatory (glutamatergic) and inhibitory (GABA-ergic) neurotransmission In addition to these neuronal effects, NRG1 can modulate the functions of peripheral immune cells. Additional evidence from animal and human studies suggests that NRG1 may be a key factor in the interplay of neurodevelopment, synaptic plasticity, glutamatergic/GABA-ergic neurotransmission, and immunological mechanisms in schizophrenia[28,29,30,31,32,33,34,35]
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