Cytokine Alterations in Schizophrenia: An Updated Review

Abstract

Schizophrenia, a multisystem disorder with an unknown etiology, is associated with several immune dysfunctions, including abnormal levels of circulating cytokines. In this review, we investigated the changes of cytokines in schizophrenic patients, their connection with behavioral symptoms severity and their potential clinical implications. We also assessed the possible causative role of abnormal cytokine levels in schizophrenia pathogenesis. Based on meta-analyses, we categorized cytokines according to their changes in schizophrenic patients into four groups: (1) increased cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, IL-12, and transforming growth factor (TGF)-β, (2) non-altered cytokines, including IL-2, IL-4, and IL-17, (3) increased or non-altered cytokines, including IL-8 and interferon (IFN)-γ, and (4) IL-10 with increased, decreased, and non-altered levels. Notably, alterations in cytokines may be variable in four different categories of SP, including first-episode and drug-naïve, first-episode and non-drug-naïve, stable chronic, and chronic in acute relapse. Furthermore, disease duration, symptoms severity, incidence of aggression, and cognitive abilities are correlated with levels of certain cytokines. Clinical implications of investigating the levels of cytokine in schizophrenic patients include early diagnosis, novel therapeutic targets development, patient stratification for choosing the best therapeutic protocol, and predicting the prognosis and treatment response. The levels of IL-6, IL-8, IFN-γ, IL-2 are related to the treatment response. The available evidence shows a potential causative role for cytokines in schizophrenia development. There is a substantial need for studies investigating the levels of cytokines before disease development and delineating the therapeutic implications of the disrupted cytokine levels in schizophrenia.

Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases

“…In schizophrenia, abnormalities such as increased activity and density of microglia and of pro-inflammatory serum cytokines have been found in many studies, including meta-analyses. Higher serum levels of IL-6, TNFα, and IL-1β have been recorded in first-episode drug-naïve patients and in chronic patients [249]. Both IL-12, required for Th1 cell differentiation and able to induce the increased production of IFNγ by macrophages, and TGFβ, with immunosuppressive and anti-inflammatory activities, are increased in the serum of schizophrenic patients [249].…”

“…Higher serum levels of IL-6, TNFα, and IL-1β have been recorded in first-episode drug-naïve patients and in chronic patients [249]. Both IL-12, required for Th1 cell differentiation and able to induce the increased production of IFNγ by macrophages, and TGFβ, with immunosuppressive and anti-inflammatory activities, are increased in the serum of schizophrenic patients [249]. These data confirm the importance of neuroinflammation in the genesis and evolution of the psychosis and that a complex cytokine trafficking underlies it.…”

“…Further knowledge on the immunological mechanisms underlying these pathologies may lead to common therapeutic strategies, aimed at modulating the inflammatory response underlying these disorders. [203,204] Schizophrenia [249] PTSD [270] ASD [283] TGFβ C-X-C motif chemokine 12 (stromal cell-derived factor 1) Chemoattractant for lymphocytes, macrophages, hematopoietic cells. In neuroinflammation attraction of leukocytes across the blood brain barrier.…”

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…Such ROS include, among others, hydrogen peroxide H 2 O 2 , which is a weak oxidant and a weak reducer [82]. As a result of reaction with metal ions (all group D metals except zinc, e.g., iron and copper), it creates highly reactive radicals including HO • in Fenton reaction [7,83], whose role in free radical damage to schizophrenic patients was mentioned above. As a result of the direct action of hydrogen peroxide, the structures of heme proteins are modified with the release of iron.…”

“…Changes in TLR4 levels affect the change in neuroplasticity, learning ability, and memory [80][81][82]. Currently conducted studies on the level of cytokines before and during the development of the disease aim to outline the therapeutic implications of the distortion of their levels and the usefulness of monitoring their concentration in schizophrenia [83].…”