Abstract
A number of studies have shown pharmacologic evidence indicating that stimulation of type I dopamine receptor (DR), favors T-helper-17 (Th17)-mediated immunity involved in experimental autoimmune encephalomyelitis (EAE) and in some other inflammatory disorders. Nevertheless, the lack of drugs that might discriminate between DRD1 and DRD5 has made the pharmacological distinction between the two receptors difficult. We have previously shown genetic evidence demonstrating a relevant role of DRD5-signaling in dendritic cells (DCs) favoring the CD4+ T-cell-driven inflammation in EAE. However, the role of DRD5-signaling confined to CD4+ T-cells in the development of EAE is still unknown. Here, we analyzed the functional role of DRD5-signaling in CD4+ T-cell-mediated responses and its relevance in EAE by using a genetic approach. Our results show that DRD5-signaling confined to naive CD4+ T-cells exerts a pro-inflammatory effect promoting the development of EAE with a stronger disease severity. This pro-inflammatory effect observed for DRD5-signaling in naive CD4+ T-cells was related with an exacerbated proliferation in response to T-cell activation and to an increased ability to differentiate toward the Th17 inflammatory phenotype. On the other hand, quite unexpected, our results show that DRD5-signaling confined to Tregs strengthens their suppressive activity, thereby dampening the development of EAE manifestation. This anti-inflammatory effect of DRD5-signaling in Tregs was associated with a selective increase in the expression of glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), which has been described to play a critical role in the expansion of Tregs. Our findings here indicate a complex role for DRD5-signaling in CD4+ T-cells-driven responses potentiating early inflammation mediated by effector T-cells in EAE, but exacerbating suppressive activity in Tregs and thereby dampening disease manifestation in late EAE stages.
Highlights
During last 15 years dopamine has emerged as a major regulator of inflammation
Since we previously appreciated a difference in the severity of EAE manifestation between animals deficient in DRD5 confined to dendritic cells (DCs) and animals displaying a global deficiency of DRD5 (Prado et al, 2012), we wondered whether DRD5-signaling in other immune cells was relevant in the regulation of the inflammatory response involved in EAE
Values represent mean ± SEM with n = 5–6 mice per group. ∗∗p < 0.01 by Mann-Whitney U-test. (B) EAE was induced in WT and DRD5 knockout (DRD5KO) mice by immunization with peptide MOG35–55 (pMOG) in complete Freund’s adjuvant (CFA) followed by Pertussis Toxin injection and disease severity was daily determined throughout the time-course of disease development
Summary
During last 15 years dopamine has emerged as a major regulator of inflammation. All five dopamine receptors (DRs, DRD1DRD5) have been found to be expressed in immune cells, including dendritic cells (DCs) and T-cells among others, where they exert a complex regulation of immunity (Pacheco et al, 2014). Emerging evidence has shown a relevant role of type I DRs (including DRD1 and DRD5) in the regulation of CD4+ T-cellmediated autoimmune response involved in human individuals undergoing MS and in EAE (Prado et al, 2013). In this regard, type I DRs have been described to be expressed in DCs (Nakano et al, 2008; Prado et al, 2012) and CD4+ T-cells from human and mouse origin (Kipnis et al, 2004; Cosentino et al, 2007; Kim et al, 2013; Franz et al, 2015)
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