Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2,3-dioxygenase 1

Murakami, Yuki; Ishibashi, Takehiko; Tomita, Eiichi; Imamura, Yukio; Tashiro, T; Watcharanurak, Kanitta; Nishikawa, Makiya; Takahashi, Yuki; Takakura, Yoshinobu; Mitani, Satoko; Fujigaki, Hidetsugu; Ohta, Yoshiji; Kubo, Hisako; Mamiya, Takayoshi; Nabeshima, Toshitaka; Kim, Hyoung Chun; Yamamoto, Yorimasa

doi:10.1038/srep29920

Cited by 45 publications

(42 citation statements)

References 61 publications

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“…Elevated DO activity ( Kynurenine Pathway activation) is linked to both human depression and murine depression-like symptomology (Baranyi et al, 2015; Murakami et al, 2016; O’Connor et al, 2009b; O’Connor et al, 2009c). Although the Kynurenine Pathway is associated with depression, there has been no work suggesting that anti-depressant activity involves modulation of the Kynurenine Pathway .…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have suggested that Ido1 in dendritic (Munn et al, 2002) and NK cells (Kai et al, 2004) produce Kyn to modulate the peripheral immune system (Lippens et al, 2016; Maldonado and von Andrian, 2010; Munn et al, 2002; Murakami et al, 2013). Clinical studies suggest a link between this response and depression (Baranyi et al, 2015; Murakami et al, 2016), connecting peripheral DO activity and MDD. Since Ido1-FL expression by PBMCs was increased in response to LPS ( in vivo ) and IFNγ ( ex vivo ) and blocked by Desip, our work clearly shows that Desip diminishes both CNS and peripheral DO expression.…”

Section: Discussionmentioning

confidence: 99%

“…A subset of individuals with major depressive disorder present with evidence of an activated immune system (increased inflammatory biomarkers) and another subset have increased peripheral tryptophan metabolism to kynurenine (Kyn) (Murakami et al, 2016; Raison and Miller, 2011). In patients with chronic elevation of inflammatory markers, anti-inflammatory drugs have potential anti-depressant efficacy (Raison, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Three rate-limiting dioxygenase enzymes (DO’s: indoleamine-dioxygenases Ido1 and Ido2, plus tryptophan-2,3-dioxygenase (Tdo2)) metabolize tryptophan into N-formyl-kynurenine that is then metabolized into Kyn. In human studies, up to 45% of patients with hepatitis C or cancer have a greater severity of depression symptoms following immunotherapy with IFNα (Capuron et al, 2002; Constant et al, 2005; Raison et al, 2009) with severity of depression symptoms associated with elevated Kyn production (Murakami et al, 2016; Raison et al, 2010), while lipopolysaccharide (LPS) administration to subjects induced inflammation and a depression phenotype (Reichenberg et al, 2001). These studies reveal that elevated inflammatory markers are linked to MDD and provide direct evidence that inflammation and the Kynurenine Pathway are linked to depressive symptomology (Dowlati et al, 2010; Galecki et al, 2012; Kappelmann et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of the Kynurenine Pathway is associated with induction of inflammation-induced depression (Murakami et al, 2016; Raison and Miller, 2011). Expression and regulation of the DOs indicate that enhanced DO activity and elevated DO expression are correlated with depression symptomology in both human and rodent models (Brooks et al, 2016b; Capuron et al, 2002; O’Connor et al, 2009a).…”

Section: Introductionmentioning

confidence: 99%

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Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

Brooks

Janda

Lawson

et al. 2017

Brain, Behavior, and Immunity

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Abundant evidence connects depression symptomology with immune system activation, stress and subsequently elevated levels of kynurenine. Anti-depressants, such as the tricyclic norepinephrine/serotonin reuptake inhibitor desipramine (Desip), were developed under the premise that increasing extracellular neurotransmitter level was the sole mechanism by which they alleviate depressive symptomologies. However, evidence suggests that anti-depressants have additional actions that contribute to their therapeutic potential. The Kynurenine Pathway produces tryptophan metabolites that modulate neurotransmitter activity. This recognition identified another putative pathway for anti-depressant targeting. Considering a recognized role of the Kynurenine Pathway in depression, we investigated the potential for Desip to alter expression of rate-limiting enzymes of this pathway: indoleamine-2,3-dioxygenases (Ido1 and Ido2). Mice were administered lipopolysaccharide (LPS) or synthetic glucocorticoid dexamethasone (Dex) with Desip to determine if Desip alters indoleamine-dioxygenase (DO) expression in vivo following a modeled immune and stress response. This work was followed by treating murine and human peripheral blood mononuclear cells (PBMCs) with interferon-gamma (IFNγ) and Desip. In vivo: Desip blocked LPS-induced Ido1 expression in hippocampi, astrocytes, microglia and PBMCs and Ido2 expression by PBMCs. Ex vivo: Desip decreased IFNγ-induced Ido1 and Ido2 expression in murine PBMCs. This effect was directly translatable to the human system as Desip decreased IDO1 and IDO2 expression by human PBMCs. These data demonstrate for the first time that an anti-depressant alters expression of Ido1 and Ido2, identifying a possible new mechanism behind anti-depressant activity. Furthermore, we propose the assessment of PBMCs for anti-depressant responsiveness using IDO expression as a biomarker.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

Brooks

Janda

Lawson

et al. 2017

Brain, Behavior, and Immunity

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Type I interferon pathway in CNS homeostasis and neurological disorders

Blank

Prinz

2017

Glia

126

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Type I interferons (IFNs), IFN-α and IFN-β, represent the major effector cytokines of the host immune response against viruses and other intracellular pathogens. These cytokines are produced via activation of numerous pattern recognition receptors, including the Toll-like receptor signaling network, retinoic acid-inducible gene-1 (RIG-1), melanoma differentiation-associated protein-5 (MDA-5) and interferon gamma-inducible protein-16 (IFI-16). Whilst the contribution of type I IFNs to peripheral immunity is well documented, they can also be produced by almost every cell in the central nervous system (CNS). Furthermore, IFNs can reach the CNS from the periphery to modulate the function of not only microglia and astrocytes, but also neurons and oligodendrocytes, with major consequences for cognition and behavior. Given the pleiotropic nature of type I IFNs, it is critical to determine their exact cellular impact. Inappropriate upregulation of type I IFN signaling and interferon-stimulated gene expression have been linked to several CNS diseases termed "interferonopathies" including Aicardi-Goutieres syndrome and ubiquitin specific peptidase 18 (USP18)-deficiency. In contrast, in the CNS of mice with virus-induced neuroinflammation, type I IFNs can limit production of other cytokines to prevent potential damage associated with chronic cytokine expression. This capacity of type I IFNs could also explain the therapeutic benefits of exogenous type I IFN in chronic CNS autoimmune diseases such as multiple sclerosis. In this review we will highlight the importance of a well-balanced level of type I IFNs for healthy brain physiology, and to what extent dysregulation of this cytokine system can result in brain 'interferonopathies'.

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Astroglial major histocompatibility complex class I following immune activation leads to behavioral and neuropathological changes

Sobue

Ito

Nagai

et al. 2018

Glia

Self Cite

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In the central nervous system, major histocompatibility complex class I (MHCI) molecules are mainly expressed in neurons, and neuronal MHCI have roles in synapse elimination and plasticity. However, the pathophysiological significance of astroglial MHCI remains unclear. We herein demonstrate that MHCI expression is up-regulated in astrocytes in the medial prefrontal cortex (mPFC) following systemic immune activation by an intraperitoneal injection of polyinosinic-polycytidylic acid (polyI:C) or hydrodynamic interferon (IFN)-γ gene delivery in male C57/BL6J mice. In cultured astrocytes, MHCI/H-2D largely co-localized with exosomes. To investigate the role of astroglial MHCI, H-2D, or sH-2D was expressed in the mPFC of male C57/BL6J mice using an adeno-associated virus vector under the control of a glial fibrillary acidic protein promoter. The expression of astroglial MHCI in the mPFC impaired sociability and recognition memory in mice. Regarding neuropathological changes, MHCI expression in astrocytes significantly activated microglial cells, decreased parvalbumin-positive cell numbers, and reduced dendritic spine density in the mPFC. A treatment with GW4869 that impairs exosome synthesis ameliorated these behavioral and neuropathological changes. These results suggest that the overexpression of MHCI in astrocytes affects microglial proliferation as well as neuronal numbers and spine densities, thereby leading to social and cognitive deficits in mice, possibly via exosomes created by astrocytes.

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Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2,3-dioxygenase 1

Cited by 45 publications

References 61 publications

Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

Type I interferon pathway in CNS homeostasis and neurological disorders

Astroglial major histocompatibility complex class I following immune activation leads to behavioral and neuropathological changes

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