Activated Phosphorylated STAT1 Levels as a Biologically Relevant Immune Signal in Schizophrenia

Abstract

Objective: Activation of STAT1 is directly downstream of the cytokine receptors that signal from specific proinflammatory cytokines known to be dysregulated in schizophrenia (SZ), such as IFNγ, IL6, IL2 and IL10, as well as hypoxia, viral/bacterial infections and peptide growth factors. If the increased cytokine protein levels repeatedly observed in SZ have biological consequences, then the measurement of pSTAT1 is a logical step forward. Methods: Peripheral blood mononuclear cells (PBMCs) from controls (n = 13) and subjects with SZ (n = 22) were extracted using the Ficoll method. Participants with SZ were diagnosed using the SCID, clinical symptomatology was measured using the Positive and Negative Syndrome Scale (PANSS), and cognitive functioning was measured using the MATRICS Consensus Cognitive Battery. Levels of activated STAT1 (Y701), i.e. phosphorylated STAT1 (pSTAT1), were measured by a commercially available ELISA in nuclear extracts from PBMCs. Results: There was a significant bimodal distribution in the sample, with an SZ subgroup expressing significantly greater levels of activated pSTAT1 than the remainder of the participants. In this subgroup, levels of pSTAT1 were significantly higher than in the control group, as well as significantly higher than in the remainder of the SZ subjects. Furthermore, this subsample of patients manifested significantly poorer cognitive performance on several measures of the MATRICS. Discussion: pSTAT1 levels may provide a measure of the biological relevance of widely reported elevations in levels of cytokines in SZ over the past several decades. Activation of kinase cascades can be used to partition or disassemble the composite immune signal in patients living with SZ.

Long non-coding and endogenous retroviral RNA levels are associated with proinflammatory cytokine mRNA expression in peripheral blood cells: Implications for schizophrenia

“…Whether HERV-W expression may be a cause and/or consequence of inflammation is still the subject of debate. At least in vitro , our THP-1 cell culture results support the hypothesis that these transcripts can be secondary to inflammation, as the expression of HERV-W env and gag transcripts increased following treatment with two independent pro-inflammatory stimuli, IFN-γ and LPS, which activate the JAK-STAT1 and NF-κB signaling pathways shown to be dysregulated in individuals with schizophrenia (Sharma et al, 2016; Song et al, 2009). Interestingly, direct binding of transcription factors to HERV promoter elements following cytokine stimulation, and a subsequent increase in expression, has recently been demonstrated for the HERV-K family of endogenous retroviruses (Manghera et al, 2016).…”

“…Persistent sub-clinical inflammation, primarily characterized by elevated expression of proinflammatory cytokines, including IL-6, TNF-α and IFN- γ, is a well replicated finding in the schizophrenia literature (Chase et al, 2016, 2015; Miller et al, 2011). Additionally, we and others have shown that corresponding inflammatory cell signaling pathways (JAK-STAT1 and NF-κB) are also affected (Sharma et al, 2016; Song et al, 2009). However, the explanation for and potential pathophysiological consequences of inflammation in this disorder remain to be established.…”

C4A mRNA expression in PBMCs predicts the presence and severity of delusions in schizophrenia and bipolar disorder with psychosis

“…Altered immune system activity has been repeatedly demonstrated in individuals with schizophrenia and bipolar disorder, though a clear mechanistic understanding of the cause and consequence of immune activation remains to be elucidated (Beumer et al, 2012; Miller and Goldsmith, 2016). We have recently shown that a subset of individuals with schizophrenia have elevated levels of phosphorylated STAT1 (pSTAT1-Y701) in peripheral blood mononuclear cell (PBMC) nuclear extracts, indicating activation of the JAK/STAT1 signaling pathway (Sharma et al, 2016). This pathway is involved in the activation of myeloid cells to an inflammatory phenotype and is downstream of a number of keymembrane cytokine receptors, including interferon gamma (IFN-γ), which demonstrates altered expression in schizophrenia (Miller et al, 2011; Rauch et al, 2013).…”

Targeting the Immune System With Pharmacotherapy in Schizophrenia

“…Both the JAK-STAT1 and NF-κB pathways, which demonstrate elevated activity in schizophrenia, require defined activity by catalytic enzymes such as kinases [4, 7, 8]. JAK inhibitors, such as tofacitinib and ruxolitinib have shown efficacy in clinical trials for a number of immune disorders, and tofacitinib has been approved for use in rheumatoid arthritis [94].…”

“…Gene expression profiling of circulating peripheral blood mononuclear cells (PBMCs) also demonstrates increased mRNA expression of these cytokines [4–6]. Additionally, there is evidence that cell signaling pathways critical in inflammation, NF-κB and JAK-STAT1, are activated to a greater degree in PBMCs from some individuals with schizophrenia compared to controls [4, 7, 8]. Excess inflammation can be accompanied by oxidative and nitrosative stress, and there is evidence in schizophrenia of increased markers such as iNOS, COX-2 and PGE 2 , as well as decreased antioxidant status [9–11].…”