Dopamine, through the Extracellular Signal-Regulated Kinase Pathway, Downregulates CD4<sup>+</sup>CD25<sup>+</sup>Regulatory T-Cell Activity: Implications for Neurodegeneration

Kipnis, Jonathan; Cardon, Michal; Avidan, Hila; Lewitus, Gil M.; Mordechay, Sharon; Rolls, Asya; Shani, Yael; Schwartz, Michal

doi:10.1523/jneurosci.0600-04.2004

Cited by 176 publications

(188 citation statements)

References 50 publications

(49 reference statements)

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“…These differences in the decrease of EAE severity and in disease onset observed in D5RKO mice and WT mice transferred with D5RKO DCs may suggest that D5R signaling in cell types other than DCs is involved in the progression and development of this autoimmune disease. In this regard, Kipnis et al (52) have described that Tregs express type I DARs, and stimulation of these receptors attenuates the suppressive activity of Tregs. Thus, absence of D5R in Tregs could favor the suppressive activity of these cells and thereby contribute to decreased EAE manifestation observed in D5RKO mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

Prado

Contreras

González

et al. 2012

The Journal of Immunology

115

132

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Dendritic cells (DCs) are responsible for priming T cells and for promoting their differentiation from naive T cells into appropriate effector cells. Emerging evidence suggests that neurotransmitters can modulate T cell-mediated immunity. However, the involvement of specific neurotransmitters or receptors remains poorly understood. In this study, we analyzed the role of dopamine in the regulation of DC function. We found that DCs express dopamine receptors as well as the machinery necessary to synthesize, store, and degrade dopamine. Notably, the expression of D5R decreased upon LPS-induced DC maturation. Deficiency of D5R on the surface of DCs impaired LPS-induced IL-23 and IL-12 production and consequently attenuated the activation and proliferation of Ag-specific CD4+ T cells. To determine the relevance of D5R expressed on DCs in vivo, we studied the role of this receptor in the modulation of a CD4+ T cell-driven autoimmunity model. Importantly, D5R-deficient DCs prophylactically transferred into wild-type recipients were able to reduce the severity of experimental autoimmune encephalomyelitis. Furthermore, mice transferred with D5R-deficient DCs displayed a significant reduction in the percentage of Th17 cells infiltrating the CNS without differences in the percentage of Th1 cells compared with animals transferred with wild-type DCs. Our findings demonstrate that by contributing to CD4+ T cell activation and differentiation to Th17 phenotype, D5R expressed on DCs is able to modulate the development of an autoimmune response in vivo.

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Section: Discussionmentioning

confidence: 99%

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

Prado

Contreras

González

et al. 2012

The Journal of Immunology

115

132

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“…Regarding expression of DA receptors (DARs) in immune cells, these receptors have been found not only in cells of the innate immune response such as dendritic cells (DCs), NK cells, macrophages/monocytes and granulocytes (19)(20)(21) but also in cells of the adaptive immune response such as B cells, CD8 + T cells, and CD4 + T cells (22)(23)(24)(25)(26)(27)(28)(29)(30). Despite being lesser studied than in human T cells, DARs expression has also been described in murine T cells (26,31). Pharmacological evidence obtained from a group of studies performed with human T cells has suggested that among five DARs described so far (D1R-D5R), both type I (D1R and D5R) and type II (D2R, D3R, and D4R) contribute to the regulation of T cell function.…”

Section: P Arkinson's Disease (Pd) Is a Neurodegenerative Disordermentioning

confidence: 99%

Dopamine Receptor D3 Expressed on CD4+ T Cells Favors Neurodegeneration of Dopaminergic Neurons during Parkinson’s Disease

González

Contreras

Prado

et al. 2013

The Journal of Immunology

128

145

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Emerging evidence has demonstrated that CD4+ T cells infiltrate into the substantia nigra (SN) in Parkinson's disease (PD) patients and in animal models of PD. SN-infiltrated CD4+ T cells bearing inflammatory phenotypes promote microglial activation and strongly contribute to neurodegeneration of dopaminergic neurons. Importantly, altered expression of dopamine receptor D3 (D3R) in PBLs from PD patients has been correlated with disease severity. Moreover, pharmacological evidence has suggested that D3R is involved in IFN-γ production by human CD4+ T cells. In this study, we examined the role of D3R expressed on CD4+ T cells in neurodegeneration of dopaminergic neurons in the SN using a mouse model of PD. Our results show that D3R-deficient mice are strongly protected against loss of dopaminergic neurons and microglial activation during 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. Notably, D3R-deficient mice become susceptible to MPTP-induced neurodegeneration and microglial activation upon transfer of wild-type (WT) CD4+ T cells. Furthermore, RAG1 knockout mice, which are devoid of T cells and are resistant to MPTP-induced neurodegeneration, become susceptible to MPTP-induced loss of dopaminergic neurons when reconstituted with WT CD4+ T cells but not when transferred with D3R-deficient CD4+ T cells. In agreement, experiments analyzing activation and differentiation of CD4+ T cells revealed that D3R favors both T cell activation and acquisition of the Th1 inflammatory phenotype. These findings indicate that D3R expressed on CD4+ T cells plays a fundamental role in the physiopathology of MPTP-induced PD in a mouse model.

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“…This latter cell type, in particular CD4 + T cells, are most relevant since it was recently shown that the key role of A 2A Rs in attenuating peripheral tissue damage from ischemiaYreperfusion injury is due to the activation of A 2A Rs in CD4 + T cells [322]. Since the depletion of CD4 + YCD25 + regulatory T cells has been shown to promote survival of neurons after brain insults [323], in a manner regulated by metabotropic receptors such as dopamine D 1 receptors [324], it would be interesting to test if A 2A Rs might affect this particular population of T cells to control brain injury. However, the urgent need remains to provide a logical explanation for the fundamentally opposite effects of A 2A Rs in cell death involving inflammatory reactions in the brain and in the periphery.…”

Section: A 2a Receptor Blockade Confers Robust Neuroprotectionmentioning

confidence: 99%

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Cunha

2005

Purinergic Signalling

481

432

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Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

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Dopamine, through the Extracellular Signal-Regulated Kinase Pathway, Downregulates CD4⁺CD25⁺Regulatory T-Cell Activity: Implications for Neurodegeneration

Cited by 176 publications

References 50 publications

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

Dopamine Receptor D3 Expressed on CD4+ T Cells Favors Neurodegeneration of Dopaminergic Neurons during Parkinson’s Disease

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

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Dopamine, through the Extracellular Signal-Regulated Kinase Pathway, Downregulates CD4+CD25+Regulatory T-Cell Activity: Implications for Neurodegeneration

Cited by 176 publications

References 50 publications

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

Dopamine Receptor D3 Expressed on CD4+ T Cells Favors Neurodegeneration of Dopaminergic Neurons during Parkinson’s Disease

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

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Dopamine, through the Extracellular Signal-Regulated Kinase Pathway, Downregulates CD4⁺CD25⁺Regulatory T-Cell Activity: Implications for Neurodegeneration