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The Role of Aberrations in the Immune-Inflammatory Response System (IRS) and the Compensatory Immune-Regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: the IRS-CIRS Theory of Schizophrenia

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Abstract

Several lines of evidence indicate that aberrations in immune-inflammatory pathways may contribute to the pathophysiology of schizophrenia spectrum disorders. Here, we propose a novel theoretical framework that was previously developed for major depression and bipolar disorder, namely, the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first-episode psychosis (FEP), acute relapses, chronic and treatment-resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute-phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1β, IL-6, and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17), and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-β1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway, and chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3, and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate the activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-α receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin, and other acute-phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic, and deficit schizophrenia, indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor that may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Therefore, components of the CIRS may offer promising therapeutic targets for schizophrenia.

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Abbreviations

TRYCAT:

Tryptophan catabolite

NMDA:

N-methyl-d-aspartate

Hp:

Haptoglobin

Fb:

Fibrinogen

C3C:

Complement component 3

C4:

Complement 4

alpha 1S:

Alpha 1-acid-glycoprotein

Hpx:

Hemopexin

sIL-2R:

Soluble interleukin-2 receptor

IL:

Interleukin

IRS:

Immune-inflammatory response system

TNF-α:

Tumor necrosis factor-alpha

IFN-γ:

Interferon-gamma

Th:

T helper

iTreg:

Induced T regulatory

TGF:

Transforming growth factor

CIRS:

Compensatory immune-regulatory reflex system

FEP:

First-episode psychosis

TRS:

Treatment-resistant schizophrenia

LPS:

Lipopolysaccharides

NK cells:

Natural killer cells

CRP:

C-reactive protein

CSF:

Cerebrospinal fluid

CC:

Clara cell secretory protein

CXCL8:

Chemokine (C-X-C motif) ligand 8

CCL:

Chemokine ligands

MIP:

Macrophage inflammatory protein

IDO:

Indoleamine 2,3-dioxygenase enzyme

PANSS:

Positive and Negative Syndrome Scale

NFκB:

Nuclear factor-kappa-B

NDEL1:

Nuclear distribution protein nudE-like 1

MBP:

Myelin basic protein

COMT:

Catechol-O-methyltransferase

HERV:

Human endogenous retrovirus

GM-CSF :

Granulocyte-macrophage colony-stimulating factor

DCs:

Dendritic cells

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Funding

This study was funded by Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University, grant number RA61/016 and Chulalongkorn University; Government Budget; and by the Asahi Glass Foundation, Chulalongkorn University Centenary Academic Development Project and Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University, grant number RA60/042.

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Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Chutima Roomruangwong, Buranee Kanchanatawan & Michael Maes

  2. Schizophrenia Program (PROESQ), Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil

    Cristiano Noto

  3. GAPi (Early Psychosis Group), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil

    Cristiano Noto

  4. CRC, London, Scotland, UK

    George Anderson

  5. Department of Experimental Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland

    Marta Kubera

  6. Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Andre F. Carvalho

  7. Centre for Addiction & Mental Health (CAMH), Toronto, ON, M6J 1H4, Canada

    Andre F. Carvalho

  8. Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

    Michael Maes

  9. IMPACT Strategic Research Centre, Deakin University, Geelong, Vic, Australia

    Michael Maes

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  1. Chutima Roomruangwong
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All the contributing authors have participated in the manuscript. CR and MM designed the study. All authors contributed to the interpretation of the data and writing of the manuscript. All authors approved the final version of the manuscript.

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Roomruangwong, C., Noto, C., Kanchanatawan, B. et al. The Role of Aberrations in the Immune-Inflammatory Response System (IRS) and the Compensatory Immune-Regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: the IRS-CIRS Theory of Schizophrenia. Mol Neurobiol 57, 778–797 (2020). https://doi.org/10.1007/s12035-019-01737-z

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