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Monocyte Transcriptional Profiling Highlights a Shift in Immune Signatures Over the Course of Illness in Schizophrenia.

ABSTRACT: With advanced understanding of the intricate interplay between the immune and central nervous systems in neurological and neuropsychiatric illness, there is renewed interest in the potential contribution of immune dysregulation to the development and progression of schizophrenia. To inform this line of inquiry requires a more nuanced understanding of specific immune changes throughout the course of illness. Here, we utilized a genome-wide sequencing approach to transcriptionally profile circulating monocytes in participants with chronic schizophrenia. These myeloid cells, isolated from whole blood samples, are highly plastic with potentially important disease-modifying functions. Differential gene expression and gene set enrichment analyses, focusing on established monocyte phenotypic signatures, including those related to proinflammatory ("M1-like") and protective or tissue remodeling ("M2-like") functions, were carried out. We demonstrate an overall enrichment of both "M1-like" (interferon-alpha, interferon-gamma, lipopolysaccharide acute) and "M2-like" (endotoxin tolerance, glucocorticoid acute) monocyte signatures in the participants with schizophrenia compared to non-psychiatric controls. There was no enrichment of the "M1-like" chronic stress signature or the "M2-like" interleukin-4 signature. Using the Molecular Signatures Database Hallmark gene sets list, the "interferon response" was most strongly enriched in schizophrenia compared to controls. Additionally, an exploratory subgroup analysis based on illness duration suggests a shift in monocyte phenotype with illness progression. Specifically, the "M1-like" interferon-gamma signature shows decreased enrichment accompanied by increased enrichment of opposing "M2-like" signatures in participants with a medium illness duration shifting to a strong enrichment of interferon response signatures only in participants with a long illness duration. These findings related to circulating immune cell phenotype have potentially important implications for understanding the role of immune dysregulation in schizophrenia and are a critical consideration for future study design and immune-targeting treatment strategies.

SUBMITTER: Melbourne JK

PROVIDER: S-EPMC8160367 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAfrican animal trypanosomiasis (AAT) caused by tsetse fly-transmitted protozoa of the genus Trypanosoma is a major constraint on livestock and agricultural production in Africa and is among the top ten global cattle diseases impacting on the poor. Here we show that a functional genomics approach can be used to identify temporal changes in host peripheral blood mononuclear cell (PBMC) gene expression due to disease progression. We also show that major gene expression differences exist between cattle from trypanotolerant and trypanosusceptible breeds. Using bovine long oligonucleotide microarrays and real time quantitative reverse transcription PCR (qRT-PCR) validation we analysed PBMC gene expression in naïve trypanotolerant and trypanosusceptible cattle experimentally challenged with Trypanosoma congolense across a 34-day infection time course.ResultsTrypanotolerant N'Dama cattle displayed a rapid and distinct transcriptional response to infection, with a ten-fold higher number of genes differentially expressed at day 14 post-infection compared to trypanosusceptible Boran cattle. These analyses identified coordinated temporal gene expression changes for both breeds in response to trypanosome infection. In addition, a panel of genes were identified that showed pronounced differences in gene expression between the two breeds, which may underlie the phenomena of trypanotolerance and trypanosusceptibility. Gene ontology (GO) analysis demonstrate that the products of these genes may contribute to increased mitochondrial mRNA translational efficiency, a more pronounced B cell response, an elevated activation status and a heightened response to stress in trypanotolerant cattle.ConclusionThis study has revealed an extensive and diverse range of cellular processes that are altered temporally in response to trypanosome infection in African cattle. Results indicate that the trypanotolerant N'Dama cattle respond more rapidly and with a greater magnitude to infection compared to the trypanosusceptible Boran cattle. Specifically, a subset of the genes analyzed by real time qRT-PCR, which display significant breed differences, could collectively contribute to the trypanotolerance trait in N'Dama.

Project description:ObjectiveSchizophrenia poses a tremendous health, social, and economic burden upon patients and society, indicating current treatment options remain inadequate. Recent findings from several lines of evidence have pointed to the importance of immune system involvement in not only premorbid neurodevelopmental but also subsequent symptom generation and aging processes of brain change in schizophrenia. In this meta-review, we use the summarized evidence from recent quantitative systematic reviews (SRs) and meta-analyses of several subspecialties to critically evaluate the hypothesis that immune-related processes shape the symptomatic presentation and illness course of schizophrenia, both directly and indirectly through altered neuroplasticity.MethodsWe performed a data search in PubMed for English language SRs and meta-analyses from 2010 to 2017. The methodological quality of the SRs was assessed with the AMSTAR instrument. In addition, we review in this paper 11 original publications on translocator protein (TSPO) positron emission tomography (PET) imaging in schizophrenia.ResultsWe reviewed 26 SRs and meta-analyses. Evidence from clinical observational studies of inflammatory or immunological markers and randomized controlled drug trials of immunomodulatory compounds as add-on in the treatment of schizophrenia suggests psychotic exacerbations are accompanied by immunological changes different from those seen in non-acute states, and that the symptoms of schizophrenia can be modified by compounds such as non-steroidal anti-inflammatory drug and minocycline. Information derived from post-mortem brain tissue analysis and PET neuroimaging studies to evaluate microglial activation have added new perspectives to the available evidence, yet these results are very heterogeneous. Each research domain comes with unique opportunities as well as inherent limitations. A better understanding of the (patho-)physiology of microglial cells and their role in neuroplasticity is key to interpreting the immune-related findings in the context of schizophrenia illness exacerbations and progression.ConclusionEvidence from clinical studies analyzing patients' blood and cerebrospinal fluid samples, neuroimaging and post-mortem brain tissue suggests that aberrant immune responses may define schizophrenia illness' course through altered neuroplasticity representing abnormal aging processes. Most findings are however prone to bias and confounding, and often non-specific to schizophrenia, and a multidisciplinary translational approach is needed to consolidate these findings and link them to other schizophrenia hypotheses.

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Monocyte Transcriptional Profiling Highlights a Shift in Immune Signatures Over the Course of Illness in Schizophrenia.

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