Neuroinflammation in Schizophrenia: The Key Role of the WNT/β-Catenin Pathway

Abstract

Schizophrenia is a very complex syndrome involving widespread brain multi-dysconnectivity. Schizophrenia is marked by cognitive, behavioral, and emotional dysregulations. Recent studies suggest that inflammation in the central nervous system (CNS) and immune dysfunction could have a role in the pathogenesis of schizophrenia. This hypothesis is supported by immunogenetic evidence, and a higher incidence rate of autoimmune diseases in patients with schizophrenia. The dysregulation of the WNT/β-catenin pathway is associated with the involvement of neuroinflammation in schizophrenia. Several studies have shown that there is a vicious and positive interplay operating between neuroinflammation and oxidative stress. This interplay is modulated by WNT/β-catenin, which interacts with the NF-kB pathway; inflammatory factors (including IL-6, IL-8, TNF-α); factors of oxidative stress such as glutamate; and dopamine. Neuroinflammation is associated with increased levels of PPARγ. In schizophrenia, the expression of PPAR-γ is increased, whereas the WNT/β-catenin pathway and PPARα are downregulated. This suggests that a metabolic-inflammatory imbalance occurs in this disorder. Thus, this research's triptych could be a novel therapeutic approach to counteract both neuroinflammation and oxidative stress in schizophrenia.

Keywords: PPARα; PPARγ; WNT/β-catenin pathway; glutamate; neuroinflammation; oxidative stress; schizophrenia.

Figure 1

Schematic representation of the mechanism for the interaction between neuroinflammation and oxidative stress in schizophrenia. A vicious circle can occur in which these processes stimulate each other, leading to psychotic symptoms.

Figure 2

Interaction between neuroinflammation, glutamate pathway, dopamine pathway, and subsequent stimulation of positive and negative symptoms in schizophrenia.

Figure 3

Mechanisms of interaction between neuroinflammation and the WNT/β-catenin pathway in schizophrenia. The decrease in the WNT/β-catenin pathway is associated with the increase in both DKK1 and GSK-3 β and their inhibitors; the stimulation of IL-6 and IL-8 expression; and a decrease in the expression of IL-10, an antagonist marker of inflammation. The decrease in WNT/β-catenin leads to the upregulation of PPARγ but the downregulation of PPAR α. An increase in the expression of PPARγ leads to the involvement of neuroinflammation.