The emergence of neurotransmitters as immune modulators

Franco, Rafael; Pacheco, Rodrigo; Lluı́s, Carmen; Ahern, Gerard P.; O’Connell, Peta J.

doi:10.1016/j.it.2007.07.005

Cited by 122 publications

(98 citation statements)

References 65 publications

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“…Our observations in the spleen are in line with those findings suggesting that nerve signals participate in the regulation of the humoral immune response in several organs by similar mechanisms. The nature of the neurotransmitter released upon vagus nerve stimulation (VNS) in the spleen was not determined directly, but norepinephrine is the predominant neurotransmitter released by splenic nerves (36) and this neurotransmitter is capable of altering B-cell function in vitro (24,25,37,38).…”

Section: Discussionmentioning

confidence: 99%

Neural Signaling in the Spleen Controls B-Cell Responses to Blood-Borne Antigen

Mina‐Osorio

Rosas-Ballina

Valdés-Ferrer

et al. 2012

Mol Med

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Entry of blood-borne pathogens into the spleen elicits a series of changes in cellular architecture that culminates in the systemic release of protective antibodies. Despite an abundance of work that has characterized these processes, the regulatory mechanisms that coordinate cell trafficking and antibody production are still poorly understood. Here, marginal zone (MZ) B cells responding to streptococcus in the blood were observed to migrate along splenic nerves, arriving at the red pulp venous sinuses where they become antibody-secreting cells. Electrical stimulation of the vagus nerve, which in turn regulates the splenic nerve, arrested B-cell migration and decreased antibody secretion. Thus, neural circuits regulate the first wave of antibody production following B-cell exposure to blood-borne antigen.

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Section: Discussionmentioning

confidence: 99%

Neural Signaling in the Spleen Controls B-Cell Responses to Blood-Borne Antigen

Mina‐Osorio

Rosas-Ballina

Valdés-Ferrer

et al. 2012

Mol Med

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“…During the past two decades, several studies have shown the capability of several neurotransmitters to regulate the function and differentiation of immune cells, including acetyl-choline, serotonin, glutamate, and dopamine (DA) among others (11)(12)(13)(14)(15)(16)(17)(18). 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).…”

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

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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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“…Such properties enable these cells to release neurotransmitters in the presence of certain stimuli. These neurotransmitters may act in an autocrine/paracrine manner to modulate DC function (37,40). We investigated the expression of key enzymes necessary for biosynthesis, degradation, uptake, and storage of DA in DCs.…”

Section: Dcs Express Functional D5r Whose Expression Is Modulated Durmentioning

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

Self Cite

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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The emergence of neurotransmitters as immune modulators

Cited by 122 publications

References 65 publications

Neural Signaling in the Spleen Controls B-Cell Responses to Blood-Borne Antigen

Neural Signaling in the Spleen Controls B-Cell Responses to Blood-Borne Antigen

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

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

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