Critical role of metabotropic glutamate receptor 4 in bone marrow-derived dendritic cells in the Th17 cell differentiation and the melanogenesis of B16 cells

Abstract

Vitiligo is an acquired pigmentary disorder resulting from selective destruction of melanocytes. Emerging studies have suggested that T helper cell 17 (Th17) is potentially implicated in vitiligo development and progression. It was recently discovered that metabotropic glutamate receptor 4 (mGluR4) can modulate Th17-mediated adaptive immunity. However, the influence of mGluR4 on melanogenesis of melanocytes has yet to be elucidated. In the present study, we primarily cultured mouse bone marrow-derived dendritic cells (BMDC) and then knocked down and over-expressed mGluR4 using transfection. Transduced BMDC were co-cultured with CD4 + T cells and the expression of Th17-related cytokines were measured. The morphology and melanogenesis of B16 cells were observed after being treated with co-culture medium of CD4 + T cells and transduced BMDC. We found that mGluR4 knockdown did not affect the co-stimulatory CD80 and CD86 upregulation after lipopolysaccharide stimulation but did increase the expression of Th17-related cytokines, and further down-regulated the expression of microphthalmia-associated transcription factor (MITF) and the downstream genes, decreased melanin production, and destroyed the morphology of B16 cells. Conversely, over-expression of mGluR4 reduced the expression of CD80 and CD86, suppressed the production of Th17-related cytokines, increased the expression of MITF, and did not destroy the morphology of B16 cells. Our study confirmed that mGluR4 modulated the Th17 cell polarization and resulted in the alteration of melanogenesis and morphology of B16 cells. Collectively, these findings suggest mGluR4 might be a potent target involved in the immune pathogenesis of vitiligo.

The role of glutamate receptors in the regulation of the tumor microenvironment

“…The activation of mGluR4 can regulate the Th17 immune response. mGluR4 is expressed by dendritic cells (DCs) ( 118 , 119 ). As antigen-presenting cells, DCs are very important in the communication between innate and adaptive immune systems.…”

“…The production of TGF-β, IL-6, and IL-23 induces the differentiation of naive T cells into Th17 cells, which are involved in immunity against fungi and extracellular bacteria ( 120 ). The overexpression of mGluR4 in DCs was correlated with the decreased expression of CD80 and CD86, whereas the knockdown of mGluR4 did not influence the expression of CD80 and CD86, but increased the production of IL-17A by bone-marrow-derived dendritic cells (BMDC) together with the increased production of IL-6 and IL-23 ( 118 ). As previously reported, mGluR4 could regulate cAMP leading to the regulation of the response of DCs.…”

“…In melanocytes, Th17 cytokines can regulate the microphthalmia-associated transcription factor (MITF). Treatment of DCs with Th17-related cytokines decreases the expression of MIFT and decreases melanin production in B16F10 cells ( 118 ). The regulation of DCs by mGluR4 could exert beneficial effects on the antitumor immune response.…”

Role of Amine Neurotransmitters and Their Receptors in Skin Pigmentation: Therapeutic Implication

“…T helper cell 17 (Th17) has been reported to be potentially linked to the development and progression of vitiligo. In other words, GRM4 regulates the polarisation of T17 cells and alters the melanin production and morphology of B16 cells [ 203 ].…”

Myron Gordon Award paper: Microbes, T‐cell diversity and pigmentation

“…Both the abundance of CD8 T cells and the presence of IFN‐γ suggest a Th1‐dominated response in vitiligo. However, there is also controversial support for the involvement of Th17‐related cytokines (Zhao et al., 2020). Some report an increased abundance of IL‐17 in active vitiligo (Zhou et al., 2015), whereas others do not (Strassner et al., 2017).…”