The Role Of Pro-Inflammatory Cytokines In The Neuroinflammation & Neurogenesis Of Schizophrenia

The following is a summary of Na KS, Jung HY, Kim YK. The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:277–86, which was developed independently of the article authors.

• Many factors are currently thought to contribute to the development of schizophrenia, such as the interactions between genetic susceptibility and environmental stressors during early development.
• Neurodegeneration and inflammation may also play causative roles or act as mediating factors associated with the development of schizophrenia.
• Several studies have demonstrated signs of neurodegeneration in patients with schizophrenia, including both cortical gray matter loss and hypofunctioning of the dorsolateral prefrontal cortical region of the brain.

• The aim of this article was to review the potential role of cytokines on neuroinflammation and neurogenesis, and the consequences that these processes may have on the development of schizophrenia.

• The authors conducted a comprehensive literature review of neuroinflammation and pro-inflammatory cytokine alterations in schizophrenia, interactions between neuroinflammation and neurogenesis that may affect the development of schizophrenia, and novel pharmacological approaches to treat patients with this disease.

• Cytokines are produced by peripheral immune cells as well as by glial cells and neurons in the central nervous system (CNS).
  • They are composed of small glycoproteins that mediate signaling activities between components of the immune system and neuronal cells.
• In the periphery, changes in pro-inflammatory cytokines have been reported in patients with schizophrenia.
  • Studies have suggested that cytokines produced by type 1 T helper cells (Th1 cells), such as interleukin-2 and interleukin-12 are decreased, whereas type 2 T helper cell (Th2)-produced cytokines, such as interleukin-10 are increased in this patient group.
  • A Th1/Th2 imbalance hypothesis has been suggested in patients with schizophrenia, although two recent meta-analyses have reported that there is currently insufficient evidence to support this idea.
• It has further been noted that the elevation of peripheral cytokines may not necessarily be associated with CNS inflammation.
  • Changes in peripheral cytokine levels may be attributed to other factors such as obesity or glucose intolerance; the prevalence of a metabolic syndrome arising from chronic inflammation is much higher in patients with schizophrenia (22.2–60.0%) than in the general population (15.1–23.7%).
• Given the inconclusive findings observed in the peripheral immune system, neuroinflammation (ie, inflammation within the CNS) may be a more important factor in the etiology of schizophrenia.
  • Studies have shown that maternal infection (eg, influenza or rubella), increases the prevalence of schizophrenia in offspring, and exposure to high levels of maternal interleukin-8 can lead to abnormal neuroanatomic structures in the fetus.
• Neurogenesis is the complex process of generating new neurons, and newly-generated neurons in adulthood are thought to play a role in synaptic plasticity, cognitive functioning, and, psychiatric diseases such as depression and schizophrenia.
  • Abnormal neurogenesis has been demonstrated in post-mortem assessments of patients with schizophrenia, and neuroimaging studies have shown a decrease in volume of key regions in the brain in this patient group.
  • The gene disrupted-in-schizophrenia 1 (DISC-1) may be one of the most widely investigated candidate genes for schizophrenia, and its dysfunction has been associated with excessive acceleration of neurogenesis followed by dendritic outgrowth, ectopic apical dendrites, and soma hypertrophy.
• Interactions between neuroinflammation and neurogenesis may occur, as pro-inflammatory cytokines have effects on synaptic plasticity, neurotransmission, and neurogenesis.
  • Microglia and pro-inflammatory cytokines are capable of enhancing either neuroprotective or neurotoxic effects; their exact actions are typically based on complex signals within their microenvironment.
  • Some of these actions may be mediated interleukin-6, which plays an important role in microglial activation and has been shown to inhibit neurogenesis.
• Genetic studies support the association of inflammation and neurogenesis.
  • An interaction between Interleukin-1β and neuregulin-1 (NRG-1) has been shown to increase the risk of schizophrenia and shorten the age of disease onset.
  • In addition, a mutation in NRG-1 increases activation of pro-inflammatory cytokines in patients with schizophrenia.
• Dysregulation of dopaminergic neurotransmission and reducedN-methyl-D-aspartate (NMDA) receptor activity have been regarded as core mechanisms underlying schizophrenia.
  • Neuroinflammation may lead to elevated levels of kynurenic acid, an amino acid intermediate that can act as an NMDA receptor inhibitor.
• Given the association between inflammation and schizophrenia, antipsychotics would be expected to have an anti-inflammatory effect. However, the anti-inflammatory effects of antipsychotic medications are varied and not well characterized.

• Neurogenesis and neuroinflammation appear to play important roles in the development of schizophrenia.
• The mechanistic role of pro-inflammatory cytokines in the etiology of schizophrenia, however, has yet to be accurately determined.
• Overall, there remains a lack of specific evidence to support neurodegenerative mechanisms for schizophrenia, and further research in this area is warranted.
• Further study is required to determine the role of cytokines in the etiopathology of schizophrenia, and how these interactions may differ from other psychotic disorders. This may, in turn, inform novel pharmacological approaches for treating patients with this disease.

This summation has been developed independently of the authors. No disclosures were reported in the original article.