Cytokine Imbalance in Schizophrenia. From Research to Clinic: Potential Implications for Treatment

Abstract

Cytokines are one of the most important components of the immune system. They orchestrate the brain's response to infectious and other exogenous insults and are crucial mediators of the cross-talk between the nervous and immune systems. Epidemiological studies have demonstrated that severe infections and autoimmune disorders, in addition to genetic predisposition, are risk factors for schizophrenia. Furthermore, maternal infection during pregnancy appears to increase the risk of schizophrenia, and proinflammatory cytokines may be negatively involved in the neurodevelopmental process. A cytokine imbalance has been described in the blood and cerebrospinal fluid of schizophrenia patients, particularly in the T helper type 1 [Th1] and type 2 [Th2] cytokines, albeit the results of such studies appear to be contradictory. Chronic stress, likewise, appears to contribute to a lasting proinflammatory state and likely also promotes the disorder. The aim of this mini-review is to investigate the roles of different cytokines in the pathophysiology of schizophrenia and define how cytokines may represent key molecular targets to regulate for the prevention and treatment of schizophrenia. How current antipsychotic drugs impact cytokine networks is also evaluated. In this context, we propose to change the focus of schizophrenia from a traditionally defined brain disorder, to one that is substantially impacted by the periphery and immune system.

Decreased Brain pH and Pathophysiology in Schizophrenia

“…Thus, the drugs exert additional effects on the already dysfunctional mitochondria, accounting for increased lactate levels and decreased pH observed after chronic antipsychotic drug treatments discussed in the above section. In addition, abnormal oxidative reactions in mitochondria constantly produce reactive oxygen species (ROS) that induce apoptosis [51,52], inflammation [53,54], and mutations in mitochondrial DNA [55], all of which contribute to the pathogenesis of schizophrenia [11,[56][57][58][59]. The production of ROS worsens abnormal energy metabolism and can exacerbate high lactate levels [11].…”

The Therapeutic Prospects of Targeting IL-1R1 for the Modulation of Neuroinflammation in Central Nervous System Disorders

“…Contrary to many reports pointing to upregulated levels of IL-1β or IL-1Ra in schizophrenia, other studies found decreased or no significant alterations in the levels of these cytokines [140,145,146]. As such, the results and observations concerning IL-1 cytokines and their receptors are still vastly inconclusive and must be interpreted with caution [147].…”

Zika virus-induced TNF-α signaling dysregulates expression of neurologic genes associated with psychiatric disorders

“…In our study, we show that neurons mount a robust innate cytokine response to ZIKV infection, including a number of cytokines with previously established effects on behavior. A large body of evidence has established that neuroinflammation and inflammatory cytokine signaling is associated with psychiatric disorders, including major depressive disorder (91)(92)(93)(94) and schizophrenia (95)(96)(97). TNF-α is a major pleiotropic cytokine induced strongly in the CNS by ZIKV and other flaviviruses (98)(99)(100)(101).…”