Role of IL-6/RORC/IL-22 axis in driving Th17 pathway mediated immunopathogenesis of schizophrenia
Introduction
Although the precise mechanistic basis of schizophrenia remains enigmatic, the immuno-inflammatory theory of origin has gained prominence in recent years [1], [2]. Data supporting this model have been obtained from peripheral blood, cerebrospinal fluid (CSF), post-mortem brain and neuroimaging studies, both in human as well as experimental animals [3], [4], [5]. Based on the evidence of a disrupted T-cell network, such as altered percentages of T cells and aberrant synthesis of cytokines by T cells, a pivotal role of T lymphocytes which are the producers of pro-inflammatory cytokines have been demonstrated as part of the immunopathogenetic pathways of schizophrenia [6], [7], [8]. T lymphocytes are primarily classified as T helper 1 (Th1) and T helper 2 (Th2) based on the type of cytokines they produce [9]. Th cells are further classified as T regulatory (Treg) cells, follicular T cells (Thf), and T helper 17 (Th17) cells. Amongst these, Th17 cells have emerged as a crucial lineage of Th cells given their pivotal roles in the immunopathogenetic pathways of human diseases with infectious, autoimmune and inflammatory origins [10]. Th17 cells are predominantly involved in mucosal defence of gut, skin and lungs, where interleukin (IL)-22 and IL-17A and IL-17F play key roles.
The differentiation, amplification, and stabilization of Th17 cells are distinct from other Th cell subsets, and are co-ordinated by action of multiple cytokines as well as transcription factors. The key cytokines involved in differentiation of Th17 cells are transforming growth factor beta (TGF-β), IL-6 and IL-1β, while cytokines involved in its amplification and stabilization include IL-21 and IL-23. In addition to this, two transcription factors, signal transducer and activator of transcription 3 (STAT3) and retinoic acid receptor-related orphan receptor (RORγt or RORC) are crucial in the early differentiation of Th17 cells. Th17 cells preferentially produce IL-17A, IL-17F, IL-21 and IL-22; these effector cytokines play a role in mucosal defence and mediate immune response predominantly against extracellular bacteria [11].
Emerging evidence both from human and animal studies suggest that pro-inflammatory cytokines produced by Th17 cells may promote autoimmune and immuno-inflammatory reactions in a large number of diseases with immunological underpinnings [11]. Th17 cells are also being increasingly implicated in central nervous system disorders owing their ability to cross the blood brain barrier (BBB), infiltrate the brain and induce neuroinflammation [12], [13], [14]. IL-17 and IL-22 receptors are expressed on BBB endothelial cells as well as gut mucosal cells [15]; ligand binding to these receptors leads to disruption of the BBB tight junction [16]. This process seems to help transmigration of Th17 cells across the BBB [16]. BBB dysfunction in schizophrenia influences neuronal and synaptic function as well as glutamate homoeostasis and is linked to impaired efficacy of antipsychotics and treatment resistance [17].
The importance of the Th17 pathway is envisaged in various neuro-psychiatric disorders including schizophrenia, Autism spectrum disorders and depression, albeit supported by limited studies [18], [19]. Recently, we proposed Th17 pathway related possible mechanisms that may underlie the immunopathogenesis of schizophrenia [20], [21]. Commensurate with this, preliminary studies have demonstrated altered Th17 pathway elements in schizophrenia. In a recent study, an activated Th17 pathway accompanied by higher proportion of Th17 cells, elevated plasma levels of IL-17, IL-6 and interferon-gamma (IFN-γ) was demonstrated in drug naïve, first episode schizophrenia patients [19]. Further support towards a role of Th17 cells in the development of psychosis came from a study demonstrating an increased percentage of Th17 cells in adults with both psychotic symptoms and the 22q11.2 deletion syndrome. Th17 cell percentage was especially correlated to the presence of positive psychotic symptoms [22]. Another study showing significantly increased levels of growth-regulated oncogene (GRO), monocyte chemoattractant protein-1 (MCP-1), macrophage-derived chemokine (MDC) and soluble CD40 ligand (sCD40L) and decreased levels of IFN-γ, IL-2, IL-12p70 and IL-17 indicated a potential role of the IL-17 pathway in schizophrenia [23]. In addition, plasma levels of cytokines belonging to the Th17 pathway like IL-17, TGF-β1 and IL-23 were higher in patients with schizophrenia, and correlated with severity and aggressive behaviour [24].
Despite these advances, the precise role of the Th17 pathway is not adequately known. It is essential to determine the status of all the cytokines belonging to the Th17 pathway and the influence of transcription factors (STAT3 and RORC) on the Th17 pathway in schizophrenia. Further, examination of the effect of genetic variations within the IL17A gene on gene expression as well as plasma levels of IL-17 is necessary to understand genetic regulation of effector functions of Th17 cells. To address these issues, we adopted an integrated biochemical, genetic variation and gene expression study in drug naïve schizophrenia patients. The biochemical evaluation of Th17 pathway has been carried out by assessing the levels of fifteen cytokines belonging to the Th17 pathway.
Section snippets
Materials and methods
Schizophrenia patients (N = 221; age range: 18–45 years) attending the clinical services at the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India and fulfilling Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria were considered for this study. Amongst these, a subset of patients (n = 61) who were either drug-naïve (i.e., never treated with any psychotropic medications including antipsychotics) or drug-free (i.e. not having been treated
Results
The clinico-demographic profiles of the study subjects are summarised in (Table 1). A subset of subjects considered for cytokine estimation and gene expression studies were age- and gender matched (Table 2, Table 3).
Discussion
The pro-inflammatory cytokine data generated from experimental animals and human studies regarding the immuno-inflammatory basis of schizophrenia provided crucial clues in dissecting key elements of the pathophysiological basis of schizophrenia, at least in a subset of patients [29]. Some of the immune mediators are also being considered as markers of risk and severity of schizophrenia [30], [31]. However, most of these studies had limitations, the first being lack of data from complete panel
Conclusion
Immuno-inflammatory pathways contribute to the etiopathology of schizophrenia. The components of the Th17 pathway are increasingly being linked to the pathogenesis of various immune-inflammatory diseases and these are also being targeted for therapeutic intervention in various conditions. As an example, secukinumab, a human monoclonal antibody that targets IL-17A has efficacy signals in psoriasis and Crohn’s disease [62]. A fascinating recent case report, in which a person with treatment
Acknowledgements
MB is supported by a NHMRC Senior Principal Research Fellowship (1059660). SV is the recipient of a current Wellcome Trust-DBT India Alliance Intermediate Clinical Fellowship (Grant number IA/CPHI/15/1/502026). VS is supported by the Indian Council of Medical Research (DHR/HRD/Young Scientist/Type-VI-(2)/2015). MS is supported by UGC-RGNF.
Conflict of interest
The authors declare that they have no conflicts of interest to disclose.
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