Targeting dopamine receptor D3 signalling in inflammation

Pacheco, Rodrigo

doi:10.18632/oncotarget.14601

Cited by 36 publications

(36 citation statements)

References 7 publications

(12 reference statements)

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“…Moreover, the systemic DRD3antagonism has been shown to modulate the inflammatory response of astrocytes, attenuating microglial activation in the striatum in a mouse model of Parkinson's disease (Elgueta et al, 2017;Elgueta et al, 2019). Taken together, the current evidence indicates that high-dopamine levels promote the stimulation of lowaffinity dopamine receptors (including DRD1, DRD2, and DRD4), inducing an anti-inflammatory effect in microglia, while lowdopamine levels selectively stimulates high-affinity dopamine receptors (including DRD3 and DRD5), triggering inflammation, as proposed before (Pacheco, 2017).…”

Section: Dopaminergic Regulation Of Microglial Cellssupporting

confidence: 78%

“…Thus, the current evidence suggests an increased expression of high-affinity dopamine receptors, including DRD3 and DRD5, in Tlymphocytes of untreated schizophrenic patients, and enhanced levels of expression of the low-affinity dopamine receptor DRD2 in drug-treated schizophrenic patients. It is noteworthy that evidence obtained from in vivo approaches using animal models, or from in vitro approaches using human samples, has indicated that high affinity dopamine receptors DRD3 and DRD5 exert inflammatory effects while the low affinity dopamine receptor DRD2 promotes anti-inflammatory effects (Pacheco, 2017). Changes in dopaminergic regulation of the immune system associated to schizophrenia are integrated in Figure 1.…”

Section: Changes In Dopaminergic Regulation Of the Immune System Assomentioning

confidence: 99%

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The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

Vidal

Pacheco

2020

Front. Pharmacol.

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Dopamine is one of the neurotransmitters whose transmission is altered in a number of neural pathways in the brain of schizophrenic patients. Current evidence indicates that these alterations involve hyperactive dopaminergic transmission in mesolimbic areas, striatum, and hippocampus, whereas hypoactive dopaminergic transmission has been reported in the prefrontal cortex of schizophrenic patients. Consequently, schizophrenia is associated with several cognitive and behavioral alterations. Of note, the immune system has been found to collaborate with the central nervous system in a number of cognitive and behavioral functions, which are dysregulated in schizophrenia. Moreover, emerging evidence has associated schizophrenia and inflammation. Importantly, different lines of evidence have shown dopamine as a major regulator of inflammation. In this regard, dopamine might exert strong regulation in the activity, migration, differentiation, and proliferation of immune cells that have been shown to contribute to cognitive functions, including T-cells, microglial cells, and peripheral monocytes. Thereby, alterations in dopamine levels associated to schizophrenia might affect inflammatory response of immune cells and consequently some behavioral functions, including reference memory, learning, social behavior, and stress resilience. Altogether these findings support the involvement of an active cross-talk between the dopaminergic and immune systems in the physiopathology of schizophrenia. In this review we summarize, integrate, and discuss the current evidence indicating the involvement of an altered dopaminergic regulation of immunity in schizophrenia.

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Section: Dopaminergic Regulation Of Microglial Cellssupporting

confidence: 78%

Section: Changes In Dopaminergic Regulation Of the Immune System Assomentioning

confidence: 99%

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

Vidal

Pacheco

2020

Front. Pharmacol.

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“…At this point, naive CD8+ T cells become activated and differentiate into IFN-γ producing T helper-1(Th1) cells and cytotoxic T lymphocytes (CTLs), which exert a direct cytotoxic response on antitumor immunity. DRD3 and DRD3-signaling have been identified in DCs 83 . Of note, DRD3-deficiency and pharmacologic inhibition of DRD3 in DCs could intensify their antigen cross-presentation and CD8+ T cell activation, thus promoting a stronger CTLs response in tumor-bearing mice 84 .…”

Section: Peripheral Da and Tumor Immunitymentioning

confidence: 99%

Potential Roles of Peripheral Dopamine in Tumor Immunity

Zhang¹,

Liu²,

Liao³

et al. 2017

J. Cancer

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Recent years, immunotherapy has turned out to be a promising strategy against tumors. Peripheral dopamine (DA) has important roles in immune system among tumor patients. Accumulated reports demonstrate variable expression and distribution of DA receptors (DRs) in diverse immune cells. Interestingly, peripheral DA also involves in tumor progression and it exerts anticancer effects on immunomodulation, which includes inflammasomes in cancer, function of immune effector cells, such as T lymphocytes, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and natural killer (NK) cells. Given the specific immunologic status, DA medication may be a valuable candidate in pancreatic cancer treatment. The major purpose of this review is to discuss the novel potential interactions between peripheral dopamine and tumor immunity.

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“…In addition, DRD5-signalling in CD4 + T-cells exerted a dual role in the physiopathology of EAE, potentiating early inflammation mediated by effector T-cells, but exacerbating suppressive activity in Treg cells and thereby dampening disease manifestation in late EAE stages [35]. Although dopaminergic signalling through DRD3, which display the highest affinity for dopamine, has been strongly associated with the development and progression of inflammatory affections [43], the involvement of this receptor in the physiopathology of MS/EAE remains poorly explored.…”

Section: Introductionmentioning

confidence: 99%

“…Despite B-cells play an important role in the physiopathology of MS [7] and constitute one of the leukocyte population with the highest levels of DRs expression [44], the role of dopaminergic-stimulation in B-cells in CNS autoimmunity has not been yet studied. Indeed, B-cells have been shown to express the highest levels of DRD3 [31,44], whose stimulation has been strongly associated to inflammation [43]. Here we addressed the role of DRD3stimulation in the adaptive immune system in CNS autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

Prado

Osorio‐Barrios

Espinoza

et al. 2020

Preprint

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Background: Recent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of adaptive and innate immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Evidence from animal models has suggested that B-cells play a fundamental role as antigen-presenting cells (APC) re-stimulating CD4+ T-cells in the CNS as well as regulating T-cell response by mean of inflammatory or anti-inflammatory cytokines. Here we addressed the role of the dopamine receptor D3 (DRD3), which display the highest affinity for dopamine, in B-cells in animal models of MS.Methods: Mice harbouring Drd3-deficient or Drd3-suficient B-cells were generated by bone marrow transplantation into recipient mice devoid of B-cells. In these mice we compare the development of experimental autoimmune encephalomyelitis (EAE) induced by immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide (pMOG), a model that leads to CNS-autoimmunity irrespective of the APC function of B-cells, or by immunization with full-length human MOG protein (huMOG), a model in which antigen-specific activated B-cells display a fundamental APCs function in the CNS. Results: Our data shows that, by promoting the expression of the chemokine receptor CXCR3 in autoreactive B-cells, DRD3-stimulation favours the CNS-tropism in a subset of B-cells that act as APC in the CNS, which is fundamental for disease development. Furthermore, we found that DRD3- stimulation induced the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in a CNS-autoimmunity model independent of the APC function of B-cells.Conclusion: Our findings demonstrate that DRD3-stimulation in B-cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B-cells with APC function, and also promoting CNS-homing of B-cells with anti-inflammatory features. Thus, these results show DRD3-stimulation in B-cells as a key regulator of CNS-autoimmunity.

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Targeting dopamine receptor D3 signalling in inflammation

Cited by 36 publications

References 7 publications

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

Potential Roles of Peripheral Dopamine in Tumor Immunity

Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

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