title: Silencing IFN-γ binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity.
abstract: 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 types has opposite effects in EAE pathogenesis. Silencing IFN-γ binding/signaling in astrocytes alleviated EAE, whereas in microglia, and likely in some infiltrating macrophages, it increased disease severity. Silencing IFN-γ signaling in astrocytes resulted in diminished expression of chemokines and fewer inflammatory cells infiltrating into the CNS, whereas blocking IFN-γ binding/signaling in microglia, probably infiltrating macrophages as well, increased disease severity through augmented activation and proliferation of microglia. Further, blocking IFN-γ binding/signaling in astrocytes alleviated both Th1- and Th17-mediated adoptive EAE, indicating an important role for IFN-γ signaling in astrocytes in autoimmune CNS inflammation. Thus, our study defines novel mechanisms of action of IFN-γ in EAE pathogenesis, and also highlights an opportunity for development of multiple sclerosis therapies directed at CNS cells.
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107; Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an 710062, China;
authors: Xiaoli
authors: X
authors: Ding
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107; Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an 710062, China;
authors: Yaping
authors: Y
authors: Yan
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107;
authors: Xing
authors: X
authors: Li
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107;
authors: Ke
authors: K
authors: Li
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107;
authors: Bogoljub
authors: B
authors: Ciric
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107; Department of Pharmacology, Liaoning University of Traditional Chinese Medicine, Dalian 110847, China;
authors: Jingxian
authors: J
authors: Yang
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107;
authors: Yuan
authors: Y
authors: Zhang
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107;
authors: Shuai
authors: S
authors: Wu
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107;
authors: Hui
authors: H
authors: Xu
authors: Mucosal Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; and.
authors: Wanjun
authors: W
authors: Chen
authors: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210.
authors: Amy E
authors: AE
authors: Lovett-Racke
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107; a.m.rostami@jefferson.edu Guang-Xian.Zhang@jefferson.edu.
authors: Guang-Xian
authors: GX
authors: Zhang
authors: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107; a.m.rostami@jefferson.edu Guang-Xian.Zhang@jefferson.edu.
authors: Abdolmohamad
authors: A
authors: Rostami
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015551:Autoimmunity / Q000235:genetics*; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology* / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D018925:Chemokines; D017471:Receptors, Interferon; D007371:Interferon-gamma