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Silencing IFN-? binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity.

ABSTRACT: IFN-?, the hallmark cytokine of Th1 cells, plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Thus far, the role of IFN-? in EAE has been largely studied through its effects on immune cells, whereas much less is known about its effects on CNS cells, especially in vivo. In this study, we dissected the in vivo effects and mechanisms of IFN-? binding/signaling in astrocytes and microglia, and found that IFN-? signaling in these cell types has opposite effects in EAE pathogenesis. Silencing IFN-? binding/signaling in astrocytes alleviated EAE, whereas in microglia, and likely in some infiltrating macrophages, it increased disease severity. Silencing IFN-? signaling in astrocytes resulted in diminished expression of chemokines and fewer inflammatory cells infiltrating into the CNS, whereas blocking IFN-? binding/signaling in microglia, probably infiltrating macrophages as well, increased disease severity through augmented activation and proliferation of microglia. Further, blocking IFN-? binding/signaling in astrocytes alleviated both Th1- and Th17-mediated adoptive EAE, indicating an important role for IFN-? signaling in astrocytes in autoimmune CNS inflammation. Thus, our study defines novel mechanisms of action of IFN-? in EAE pathogenesis, and also highlights an opportunity for development of multiple sclerosis therapies directed at CNS cells.

SUBMITTER: Ding X

PROVIDER: S-EPMC4402255 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Silencing IFN-γ binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity.

Ding Xiaoli X Yan Yaping Y Li Xing X Li Ke K Ciric Bogoljub B Yang Jingxian J Zhang Yuan Y Wu Shuai S Xu Hui H Chen Wanjun W Lovett-Racke Amy E AE Zhang Guang-Xian GX Rostami Abdolmohamad A

Journal of immunology (Baltimore, Md. : 1950) 20150320 9

IFN-γ, the hallmark cytokine of Th1 cells, plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Thus far, the role of IFN-γ in EAE has been largely studied through its effects on immune cells, whereas much less is known about its effects on CNS cells, especially in vivo. In this study, we dissected the in vivo effects and mechanisms of IFN-γ binding/signaling in astrocytes and microglia, and found that IFN-γ signaling in these cell ty ...[more]

PMID: 25795755

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Project description:BackgroundRecent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of 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 displays the highest affinity for dopamine, in B cells in animal models of MS.MethodsMice harbouring Drd3-deficient or Drd3-sufficient B cells were generated by bone marrow transplantation into recipient mice devoid of B cells. In these mice, we compared 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 APC-function in the CNS. APC-function was assessed in vitro by pulsing B cells with huMOG-coated beads and then co-culturing with MOG-specific T cells.ResultsOur data show that the selective Drd3 deficiency in B cells abolishes the disease development in the huMOG-induced EAE model. Mechanistic analysis indicates that although DRD3-signalling did not affect the APC-function of B cells, DRD3 favours the CNS-tropism in a subset of pro-inflammatory B cells in the huMOG-induced EAE model, an effect that was associated with higher CXCR3 expression. Conversely, the results show that the selective Drd3 deficiency in B cells exacerbates the disease severity in the pMOG-induced EAE model. Further analysis shows that DRD3-stimulation increased the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in the pMOG-induced EAE model.ConclusionsOur findings demonstrate that DRD3 in B cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B cells with APC-function and promoting CNS-homing of B cells with anti-inflammatory features. Thus, these results show DRD3-signalling in B cells as a critical regulator of CNS-autoimmunity.

Dataset Information

Silencing IFN-? binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity.

Publications

Silencing IFN-γ binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity.

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