Bridging Autism Spectrum Disorders and Schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations

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Abstract

In recent years, evidence supporting a link between inflammation and neuropsychiatric disorders has been mounting. Autism spectrum disorders (ASD) and schizophrenia share some clinical similarities which we hypothesize might reflect the same biological basis, namely, in terms of inflammation. However, the diagnosis of ASD and schizophrenia relies solely on clinical symptoms, and to date, there is no clinically useful biomarker to diagnose or monitor the course of such illnesses.

The focus of this review is the central role that inflammation plays in ASD and schizophrenia. It spans from pre-clinical animal models to clinical research and excludes in vitro studies. Four major areas are covered: (1) microglia, the inflammatory brain resident myeloid cells, (2) biomarkers, including circulating cytokines, oxidative stress markers, and microRNA players, known to influence cellular processes at brain and immune levels, (3) effect of anti-psychotics on biomarkers and other predictors of response, and (4) impact of gender on response to immune activation, biomarkers, and response to anti-psychotic treatments.

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Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects.

Brian Miller, Peter Buckley, Wesley Seabolt … (2011)

Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation. We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) appeared to be state markers, as they were increased in AR and FEP (p < .001 for each) and normalized with antipsychotic treatment (p < .001, p = .008, and p = .005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects (p = .69). In the cerebrospinal fluid, IL-1β was significantly decreased in schizophrenia versus controls (p = .01). Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1β, IL-6, and TGF-β) may be state markers for acute exacerbations, others (IL-12, IFN-γ, TNF-α, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome.

Yiqing Yan, Wei Jiang, Lei Liu … (2015)

Inflammasomes are involved in diverse inflammatory diseases, so the activation of inflammasomes needs to be tightly controlled to prevent excessive inflammation. However, the endogenous regulatory mechanisms of inflammasome activation are still unclear. Here, we report that the neurotransmitter dopamine (DA) inhibits NLRP3 inflammasome activation via dopamine D1 receptor (DRD1). DRD1 signaling negatively regulates NLRP3 inflammasome via a second messenger cyclic adenosine monophosphate (cAMP), which binds to NLRP3 and promotes its ubiquitination and degradation via the E3 ubiquitin ligase MARCH7. Importantly, in vivo data show that DA and DRD1 signaling prevent NLRP3 inflammasome-dependent inflammation, including neurotoxin-induced neuroinflammation, LPS-induced systemic inflammation, and monosodium urate crystal (MSU)-induced peritoneal inflammation. Taken together, our results reveal an endogenous mechanism of inflammasome regulation and suggest DRD1 as a potential target for the treatment of NLRP3 inflammasome-driven diseases.

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Elevated immune response in the brain of autistic patients.

Xiaohong Li, Abha Chauhan, Ashfaq M Sheikh … (2009)

This study determined immune activities in the brain of ASD patients and matched normal subjects by examining cytokines in the brain tissue. Our results showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1 cytokine (IFN-gamma) and chemokine (IL-8) were significantly increased in the brains of ASD patients compared with the controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was also significantly increased in ASD patients. ASD patients displayed an increased innate and adaptive immune response through the Th1 pathway, suggesting that localized brain inflammation and autoimmune disorder may be involved in the pathogenesis of ASD.

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Author and article information

Contributors

Joana Prata: joanappr@gmail.com

Susana G. Santos: susana.santos@ineb.up.pt

Maria Inês Almeida: Ines.Almeida@ineb.up.pt

Rui Coelho: rmnscoelho@mail.telepac.pt

Mário A. Barbosa: mbarbosa@i3s.up.pt

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 4 September 2017

Publication date PMC-release: 4 September 2017

Publication date Collection: 2017

Volume: 14

Electronic Location Identifier: 179

Affiliations

[1 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, FMUP-Faculty of Medicine, , University of Porto, ; Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

[2 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, i3S-Instituto de Investigação e Inovação em Saúde, , University of Porto, ; Rua Alfredo Allen 208, 4200-135 Porto, Portugal

[3 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, INEB-Instituto de Engenharia Biomédica, , University of Porto, ; Rua Alfredo Allen 208, 4200-135 Porto, Portugal

[4 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, ICBAS-Instituto de Ciências Biomédicas Abel Salazar, , University of Porto, ; Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal

Article

Publisher ID: 938

DOI: 10.1186/s12974-017-0938-y

PMC ID: 5584030

PubMed ID: 28870209

SO-VID: eedd2a2b-3484-49e3-8d78-e00023279dea

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 3 March 2017

Date accepted : 8 August 2017

Funding

Funded by: Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Award ID: NORTE-01-0145-FEDER-000012

Funded by: FCT - Fundação para a Ciência e a Tecnologia

Award ID: SFRH/BPD/91011/2012

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: autism spectrum disorders,schizophrenia,inflammation,animal model,clinical research,biomarker,anti-psychotics,immune cells,microrna,microglia

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ScienceOpen disciplines: Neurosciences

Keywords: autism spectrum disorders, schizophrenia, inflammation, animal model, clinical research, biomarker, anti-psychotics, immune cells, microrna, microglia

Bridging Autism Spectrum Disorders and Schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations

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Abstract

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Biomarkers for Inflammatory Lung Disease

Most cited references 202

Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects.

Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome.

Elevated immune response in the brain of autistic patients.

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