Antagonizing dopamine D1-like receptor inhibits Th17 cell differentiation: Preventive and therapeutic effects on experimental autoimmune encephalomyelitis

Nakano, Kazuhisa; Higashi, Taishi; Hashimoto, Kumiko; Takagi, Ryukichi; Tanaka, Yoshiya; Matsushita, Sho

doi:10.1016/j.bbrc.2008.06.012

Cited by 138 publications

(199 citation statements)

References 31 publications

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“…5). Thus, although data are in agreement with a previous study (24), we were able to show that D5R specifically expressed on DCs contributes directly to CD4 + T cell fate and disease progression. In addition to the decreased disease severity, we also observed that the onset of EAE was delayed in D5RKO mice compared with that in WT mice (Fig.…”

Section: Discussionsupporting

confidence: 92%

“…In this study, the systemic treatment of mice with the type I DAR antagonist SCH alleviates the development of EAE by decreasing the Th17 response (24). However, this pharmacologic approach does not permit discrimination between the effects of D5R or D1R because the drug inhibits both type I DARs.…”

Section: Discussionmentioning

confidence: 92%

“…Therefore, systemic treatment with SCH could affect several types of immune cells. To restrict the contribution of DC signaling to the amelioration of EAE, the authors treated DCs with SCH ex vivo and transferred treated cells into WT recipient mice (24). A slight decrease in EAE severity was seen in mice transferred with SCH-treated DCs, but such differences were not statistically significant (24).…”

Section: Discussionmentioning

confidence: 99%

“…In Tregs, endogenous DA signals through D1R/D5R in a paracrine/autocrine manner resulting in the downregulation of Treg function (23). In DCs, recent pharmacological evidence suggests that the antagonism of D1R/D5R expressed on DCs could impair the polarization of naive CD4 + T cells toward the Th17 phenotype (24,25). However, as the D1R/D5R antagonist used in these studies is also an agonist for serotonin receptors (26,27) and serotonin receptors are also expressed on DCs (28), the individual contributions of specific DARs and serotonin receptors in this phenomenon are not clear (24).…”

Section: Endritic Cells (Dcs) Are the Most Efficient Type Of Apcsmentioning

confidence: 99%

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

Prado

Contreras

González

et al. 2012

The Journal of Immunology

116

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: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Endritic Cells (Dcs) Are the Most Efficient Type Of Apcsmentioning

confidence: 99%

See 2 more Smart Citations

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

Prado

Contreras

González

et al. 2012

The Journal of Immunology

116

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).…”

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

131

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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N‐glycosylation and expression in human tissues of the orphan GPR61 receptor

et al. 2017

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A number of members of the G protein‐coupled receptor class of cell surface receptors are ‘orphans’ with no known endogenous ligand. One of these orphan receptors is GPR61; there are little data about its expression in human cells and tissues. In this study, we investigated the post‐translational modification of GPR61 by N‐ glycosylation at an identified consensus N ‐glycosylation site (N12) and the impact of this modification upon the subcellular expression of the protein. The N ‐glycosylation inhibitor tunicamycin reduced the apparent molecular weight of immunoreactivity associated with myc ‐tagged GPR61 by 1–2 kDa, which was comparable to the evident molecular weight of the myc ‐tagged N12S GPR61 mutant with disrupted consensus N ‐glycosylation site. Analysis of GPR61 expression demonstrated that tunicamycin treatment reduced considerably heterologous expression of GPR61 in the cell membrane despite the N12S GPR61 mutant being readily expressed at the cell surface. These results demonstrate that GPR61 is subject to N ‐glycosylation but suggest this is not a prerequisite for cell surface expression, although N‐ glycosylation of other proteins may be important for cell membrane expression of GPR61. Expression of GPR61 protein was demonstrated at the cellular level in human hippocampus and human peripheral blood mononuclear cells. In the latter, there was a significantly higher expression of GPR61 in the Th17 cell subset in comparison with resting CD4+ cells, which may point toward a potential role for the GPR61 receptor in autoimmune diseases. This is the first report that GPR61 protein is subject to post‐translational modification and is expressed in immune cell subsets and the hippocampus. These findings will help guide studies to investigate the function of GPR61.

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Antagonizing dopamine D1-like receptor inhibits Th17 cell differentiation: Preventive and therapeutic effects on experimental autoimmune encephalomyelitis

Cited by 138 publications

References 31 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

N‐glycosylation and expression in human tissues of the orphan GPR61 receptor

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