Cytokines and schizophrenia: Microglia hypothesis of schizophrenia
Akira Monji, md, phd,* Takahiro Kato, md, phd and Shigenobu Kanba, md, phd
Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Correspondence to *Akira Monji, MD, PhD, Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. Email: amonji@hf.rim.or.jp
Copyright Journal compilation © 2009 Japanese Society of Psychiatry and Neurology
KEYWORDS
antipsychotics • cytokine • inflammation • microglia • schizophrenia
ABSTRACT
Abstract CYTOKINES AND MICROGLIA NEUROINFLAMATION IN SCHIZOPHRENIA: MICROGLIA HYPOTHESIS OF SCHIZOPHRENIA ANTIPSYCHOTICS AND MICROGLIAL ACTIVATION CONCLUSIONS REFERENCES
The etiology of schizophrenia remains unclear, while there has been a growing amount of evidence for the neuroinflammation and immunogenetics, which are characterized by an increased serum concentration of several pro-inflammatory cytokines. Despite the fact that microglia comprise only <10% of the total brain cells, microglia respond rapidly to even minor pathological changes in the brain and may contribute directly to the neuronal degeneration by producing various pro-inflammatory cytokines and free radicals. In many aspects, the neuropathology of schizophrenia has recently been reported to be closely associatedwith microglial activation. Previous studies have shown the inhibitory effects of some typical/atypical antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, both of which have recently been known to cause a decrease in neurogenesis as well as white matter abnormalities in the brains of patients with schizophrenia. The microglia hypothesis of schizophrenia may shed new light on the therapeutic strategy for schizophrenia.
Accepted 27 January 2009.
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1440-1819.2009.01945.x About DOI
Article Text
SCHIZOPHRENIA IS A chronic and often debilitating illness that affects approximately 1% of the world population. In addition to severely disrupting the life of patients and their families, schizophrenia imposes a great cost on society in terms of productivity loss and treatment-related expenses.1,2 The etiology of schizophrenia remains elusive, while dopaminergic hyperfunction in the limbic system and dopaminergic hypofunction in the frontal cortex as well as glutamatergic hypofunction are known to play important roles in the pathophysiology of schizophrenia.
We herein review the relationship between cytokines and schizophrenia. We also propose the microglia hypothesis of schizophrenia (Fig. 1), and suggest a therapeutic strategy for schizophrenia through the inhibition of microglial activation.
Figure 1. Microglia hypothesis of schizophrenia. Immunological/inflammatory activators such as interferon (IFN)-γ and lipopolysaccharide (LPS), which are induced by varieties of stress events and life events, activate microglia in the central nervous system. Activated microglia release pro-inflammatory cytokines and free radicals. These mediators are known to cause neuronal degeneration, white matter abnormalities and decreased neurogenesis. These neuron–microglia interactions may thus be one of the important factors in the pathophysiology of schizophrenia. IL, interleukin; TNF, tumor necrosis factor.
CYTOKINES AND MICROGLIA
Abstract CYTOKINES AND MICROGLIA NEUROINFLAMATION IN SCHIZOPHRENIA: MICROGLIA HYPOTHESIS OF SCHIZOPHRENIA ANTIPSYCHOTICS AND MICROGLIAL ACTIVATION CONCLUSIONS REFERENCES
Cytokines serve cellular communication. Released for auto- and paracrine signaling, membrane-associated for cell–cell interaction, or occasional biological information through body fluids, these small proteins regulate cell growth, survival, differentiation, and activities. Several cytokines, including growth factors, and their receptors have been found to be present and functional in the central nervous system (CNS).3 Among them are tumor necrosis factor-α (TNF-α), interferon (IFN), interleukin 1 (IL-1), IL-2, -3, -4, -6, -10, -12, -15, and -18, transforming growth factor-β (TGF-β), colony-stimulating factors such as macrophage colony-stimulating factor (M-CSF), platelet-derived growth factor (PDG), epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), and neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins (NT-3 and NT-4). An increasing body of evidence relates to the evergrowing family of chemokines. Neurodevelopmental roles are postulated for various cytokines. Some also modulate neuronal activities in the mature CNS and participate in neuro-immune–endocrine communication. Constitutive functions of typical immunoregulators in the day-to-day physiology of the normal immune-privileged CNS are still unclear, while certain cytokines appear in the affected brain region and the cerebrospinal fluid (CSF) when the CNS homeostasis is disturbed as a result of trauma, stroke, ischemia, infection, or degenerative processes. Increased cytokine levels in the CNS may result from blood–brain barrier (BBB) disruption or synthesis by invading immune cells, both of which originate from extraneuronal sources. Nevertheless, most, if not all, neuropathologies are to various extents associated with the activation of microglia and astrocytes. Microglia are the primary reservoirs of pro-inflammatory cytokines such as IL-6, TNF-α and IFN-γ and act as antigen-presenting cells in the CNS.4
Despite the fact that microglia comprise only <10% of the total brain cells, microglia respond rapidly to even minor pathological changes in the brain and may contribute directly to neuronal degeneration by producing various pro-inflammatory cytokines and free radicals.5,6 In contrast, the neuron–microglia interaction has been reported to orchestrate the balance between synaptogenesis and neuronal death during the brain's development and injuries.7
NEUROINFLAMATION IN SCHIZOPHRENIA: MICROGLIA HYPOTHESIS OF SCHIZOPHRENIA
Abstract CYTOKINES AND MICROGLIA NEUROINFLAMATION IN SCHIZOPHRENIA: MICROGLIA HYPOTHESIS OF SCHIZOPHRENIA ANTIPSYCHOTICS AND MICROGLIAL ACTIVATION CONCLUSIONS REFERENCES
There has been more evidence indicating the significance of neuroinflammation and immunogenetics in schizophrenia, characterized by an increased serum concentration of several pro-inflammatory cytokines.8–12 Increased serum concentrations of IL-2, IL-6 and IL-8 have been observed in schizophrenia patients,13,14 and immunomodulatory drugs such as cyclooxygenase-2 (COX-2) inhibitors have recently been reported to have beneficial effects on schizophrenia symptoms.15,16 Increased serum and CSF levels of S100B, a suitable marker for the destruction of CNS tissue in the context of different diseases including neurodegenerative disorder, were reported in schizophrenia patients with negative symptoms or a chronic duration.17 Epidemiologic studies demonstrate a significant environmental impact of maternal viral infection and obstetric complications on the risk of schizophrenia. Elevated inflammatory process is known to play an important role in these circumstances.18,19 A recent DNA microarray study has shown the increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia.8 Another recent study using the prefrontal cortex in schizophrenia has shown that the molecular basis for schizophrenia changes from early to chronic stage, providing evidence for a changing nature of schizophrenia with disease progression. Namely, short-term illness was associated with disruption in gene transcription, metal-binding, RNA expression and vesicle-mediated transport, while long-term illness was associated with inflammation, stimulus–response and immune functions.10
Microglial activation and schizophrenia
Prolonged microglial hyperactivity may lead to neuronal apoptosis and brain damage, which are commonly seen in neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD).20,21 A neurodegenerative and neurodevelopmental process is indicated in the course of schizophrenia22,23 and may be associated with microglial activation. Hypoglutamatergic states and impaired N-methyl-d-aspartate (NMDA) signaling underlie the pathophysiology of schizophrenia. NMDA antagonists such as phencyclidine (PCP), ketamine, and MK-801 offer an appropriate animal model of schizophrenia. All three NMDA antagonists are known to induce microglial activation in the brains of rodents.24,25
Interestingly, microglial activation or increased microglial cellular density has also been suggested by post-mortem studies, at least in subpopulations of individuals with schizophrenia.26–28 Highly elevated microglial cell numbers have been demonstrated in the anterior cingulate cortex and mediodorsal thalamus of patients with schizophrenia who had committed suicide during acute psychosis.29 Using [11C] ®-PK11195, a specific ligand of the peripheral benzodiazepine-binding sites (PBBS) used for a systematic study of microglial activation in vivo, researchers have recently reported increased microglial activation in the gray matter of patients with schizophrenia, which is similar to patients with neurodegenerative dementia.30,31 That positron emission computed tomography study demonstrated that activated microglia are present in schizophrenia patients within the first 5 years after the onset of disease.31
Neurogenesis and schizophrenia
The relationship between depression and neurogenesis has been described in general,32 while one recent human post-mortem brain study using Ki-67 immunoreactivity indicated that the phenomenon of neurogenesis is much more related to the pathophysiology of schizophrenia than that of depression.33 Repeated administration of PCP as well as MK-801 has recently been reported to inhibit hippocampal neurogenesis in vivo.34,35 Mice harboring compound disruption in the neuronal PAS domain protein 3 (NPAS3) and related NPAS1 genes manifest behavioral and neuroanatomical abnormalities reminiscent of schizophrenia.36 Basal neural precursor cell proliferation in the dentate gyrus of NPAS3 gene-deficient mice has been found to be reduced significantly, which indicated impaired neurogenesis involved in schizophrenia.37 Disrupted-in-schizophrenia 1 (DISC1) is a well-known schizophrenia susceptibility gene. A recent study has shown that DISC1 regulates integration of newly generated neurons in the adult brain.38 The aforementioned results indicate the close relationship between schizophrenia and neurogenesis. With regard to neurogenesis, atypical antipsychotics, but not typical antipsychotics, induced neurogenesis in the adult brains of rodents.35,39,40 In contrast, CNS inflammation is detrimental for adult hippocampal neurogenesis.41,42 The negative effects of inflammation on differentiation and survival of the neuronal cells are due, in vitro, to microglia-derived TNF-α and nitric oxide (NO).41,43 Pro-inflammatory cytokines such as Il-1β and TNF-α have been reported to inhibit neurogenesis in vivo.44,45 In addition, in vivo, neurogenesis can be restored by anti-inflammatory drugs such as minocycline and indomethacin that inhibit microglial activation.41,42
Apoptosis and schizophrenia
Structural brain abnormalities have been described extensively and consistently in schizophrenia patients. Longitudinal studies using high-resolution magnetic resonance imaging (MRI) to examine brain structure have found that MRI volume changes were progressive over time and related to the course of illness and treatment outcome in schizophrenia patients.46–48 A recent review has shown that continuous progressive brain tissue decreases, and lateral ventricle volume increases in chronically ill patients with schizophrenia, until at least 20 years after the first symptoms.49 In fact, multiple lines of evidence combine to implicate increased susceptibility to apoptotic death in the pathophysiology of schizophrenia. Reduced neuronal and glial cell numbers, decreased neuropil (especially of the synapse elements), lack of gliosis, and in vivo neuroimaging evidence of progressive gray matter loss early in the disorder, as mentioned earlier, make apoptosis a plausible mechanism to explain the neurodegenerative course of schizophrenia. The activation of apoptotic process can lead to a rapid neuronal death. Emerging data, however, also indicate that sublethal apoptotic activity can lead to a limited form of apoptosis in terminal neuritis and individual synapses to cause elimination without cell death.50,51 Inappropriate activation of apoptosis occurs not only in the neurons, but also in the oligodendrocytes and synapses.50 Pro-inflammatory cytokines such as TNF-α have been well characterized as mediators of oxidative stress, and they induced apoptosis in human cortical neuron as well as oligodendrocytes.52,53 In addition, NO has been reported not only to directly induce neuronal apoptosis, but also to be involved in cytokine-mediated neuronal apoptosis.54,55 The interaction between NO and superoxide anion (O2-), which can be generated from activated microglia, forms peroxynitrite (ONOO-). Peroxynitrite is highly toxic and triggers apoptotic cell death. Moreover, high levels of NO and TNF-α may also affect synaptogenesis, synaptic plasticity and connectivity, and the composition of synaptic membranes.56,57 The alteration in the synaptic organization of the brain is one of the key features of schizophrenia.58
Oligodendrocyte dysfunction in schizophrenia
Neuroimaging studies have shown that first-episode schizophrenia patients had a significant volume reduction in white matter with abnormal brain connectivity.59,60 The reduced density and compromised morphology of the oligodendrocytes as well as signs of deviant myelination are evident in schizophrenia.61,62 Iwamoto et al. reported a functional single-nucleotide polymorphism in the 2',3'-cyclic nucleotide 3'-phosphodiesterase gene, which affects the expression of oligodendrocyte-related genes in schizophrenia.63 Combined with the evidence of dysregulation of the myelination-related genes, a disruption of the oligodendrocyte function in schizophrenia is strongly implicated.64 Microglial activation in the CNS has been implicated in the pathogenesis of white matter disorders and it has recently been reported that microglial cytotoxicity of oligodendrocyte is mediated through free radical-related molecules such as NO and peroxynitrite generated by activated microglia,65,66 and inflammatory cytokines such as TNF-α and IFN-γ.53 In addition, TNF-α has been shown to compromise the growth of oligodendrocytes and the expression of mRNA for myelin basic protein in cultures.67 Furthermore, it inhibited the survival and proliferation of the oligodendrocyte progenitors and their subsequent differentiation into mature myelinating phenotypes.68
ANTIPSYCHOTICS AND MICROGLIAL ACTIVATION
Abstract CYTOKINES AND MICROGLIA NEUROINFLAMATION IN SCHIZOPHRENIA: MICROGLIA HYPOTHESIS OF SCHIZOPHRENIA ANTIPSYCHOTICS AND MICROGLIAL ACTIVATION CONCLUSIONS REFERENCES
Atypical antipsychotics are becoming standard drugs for the treatment of schizophrenia due to their less adverse effects and greater effectiveness for the negative symptoms of schizophrenia.48,69 Some recent reports have suggested the possibility of specific atypical antipsychotics having pharmacological properties that could produce neurotrophic, neurogenetic, or neuroprotective effects. Namely, specific atypical antipsychotics such as olanzapine and risperidone have been reported to decrease the reduction of MRI volume during the clinical course of schizophrenia.69–72 Moreover, recent reports have demonstrated that atypical antipsychotics, such as clozapine and risperidone, decreased serum levels of cytokines such as IL-2, IL-6 and TNF-α,73 the main source of which in the CNS is considered to be activated microglia in schizophrenia patients. A possible antipsychotic effect of minocycline, which is a potent inhibitor of microglial activation, has also been reported in patients with schizophrenia.74,75 Miyaoka et al., using the Positive and Negative Syndrome Scale, demonstrated statistically significant and robust clinical improvements with minocycline as an adjunctive therapy to antipsychotics for schizophrenia.74,75 We thus hypothesize that antipsychotics may have anti-inflammatory effects on microglial activation.
Typical and atypical antipsychotics with dopamine D2 receptor antagonism
To the best of our knowledge, there have been only a few previous studies on the effect of antipsychotics on microglial activation in vitro (Table 1).
Table 1. Effects of antipsychotics on microglial activation
Kowalski et al. demonstrated that flupentixol and trifluperidol reduced the secretion of TNF-α and NO by activated microglia,76 and flupentixol, trifluperidol, chlorpromazine and loxapine have been reported to reduce IL-1β and IL-2 release by activated microglia.77,78 Until recently, the pharmacological action of atypical antipsychotics on microglial cells has not been well understood. Hou et al. demonstrated that olanzapine inhibited NO release from the activated microglia, while haloperidol and clozapine did not.79 We recently demonstrated that risperidone significantly inhibited the IFN-γ-activated microglia-derived production of NO and pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in comparison to haloperidol, a typical antipsychotic.80 We furthermore demonstrated the same inhibitory effects on IFN-γ-induced microglial activation by other atypical antipsychotics such as perospirone and quetiapine.81 There have been some reports that suggested a relationship between schizophrenia and IFN-γ, a major immunoactivator in the CNS. The most important immunological studies in schizophrenia have shown that a shift from T-helper 1 (Th1)-like cellular to Th2-like humoral immune reactivity is the most characteristic common immune finding and these studies have suggested a blunted IFN-γ signal in schizophrenia.84 Rothermundt et al., however, have argued that the reduced IFN-γ production in vitro may reflect an increased production in vivo, because it is found in several autoimmune disorders.85 Furthermore, the serum levels of IL-2 and IFN-γ, and the production of these cytokines from the peripheral blood mononuclear cells stimulated by phytohemagglutinin have been reported to be significantly higher in schizophrenia patients than in controls.86 Furthermore, a recent systematic quantitative review on the inflammatory cytokine alterations in schizophrenia did not support the Th2 shift hypothesis of schizophrenia.11
Spiperone, a typical antipsychotic, also inhibited the production of NO and pro-inflammatory cytokines such as IL-1β and TNF-α from activated microglia, while spiperone was neuroprotective, because the drug reduced microglia-mediated neuroblastoma cell death in the microglia/neuron co-culture.83
Antipsychotic with dopamine D2 receptor partial agonism
Aripiprazole is a novel atypical antipsychotic, which is a high-affinity dopamine D2 receptor partial agonist. We also demonstrated that aripiprazole significantly inhibited the generation of NO and TNF-α from IFN-γ-activated microglia, while quinpirole, dopamine D2 full agonist did not.
Our results demonstrated that not only antipsychotics that have dopamine D2 receptor antagonism but also aripiprazole, a dopamine D2 receptor partial agonist, have anti-inflammatory effects via the inhibition of microglial activation.82 Microglia are known to have some kinds of neurotransmitters including dopamine D2 receptors,87 but because second generation drugs have positive effects on neuronal cell growth and survival by unique signaling pathways,88 the pharmacological basis for their neuroprotective effect appears not always to be related directly to the conventional neurotransmitter receptors.
Perspective
All of these studies suggest that some antipsychotics may therefore have a potentially useful therapeutic effect on patients with schizophrenia by reducing microglial inflammatory reactions, which may cause the apoptotic process, the inhibition of neurogenesis, and the white matter abnormalities in the brains of patients with schizophrenia. This is consistent with the evidence showing antipsychotics' influence on slowing the progressive reduction in cortical gray matter in schizophrenia.72 In contrast, microglia can secrete neurotrophic factors other than pro-inflammatory cytokines and free radicals such as BDNF. A recent study has shown that α7 nicotinic acetylcholine receptor agonist (α7nAChR) can modify microglial activation into a neuroprotective role by suppressing the inflammatory state and strengthening the protective function.89 These results are very interesting because some α7nAChR agonists are known to improve the cognitive dysfunction of schizophrenia.90 The appropriate control of microglial activation may thus be a promising therapeutic target for schizophrenia. Pro-inflammatory cytokines are also known to play important roles in the pathophysiology of depression.91 Etanercept, which is a soluble TNF-α receptor that prevents TNF-α-mediated response, has recently been reported to relieve fatigue and symptoms of depression with psoriasis.92 Immnosuppression or immunomodulatory drugs may thus be beneficial at least for the treatment of acute schizophrenia.93
CONCLUSIONS
Abstract CYTOKINES AND MICROGLIA NEUROINFLAMATION IN SCHIZOPHRENIA: MICROGLIA HYPOTHESIS OF SCHIZOPHRENIA ANTIPSYCHOTICS AND MICROGLIAL ACTIVATION CONCLUSIONS REFERENCES
In many aspects the neuropathology of schizophrenia is closely associated with microglial activation. We and other researchers have shown the inhibitory effects of some typical or atypical antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia. Our microglia hypothesis of schizophrenia (Fig. 1) may shed new light on the therapeutic strategy for schizophrenia.
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