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JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization

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单位： [1]Department of Rheumatology and Immunology,Tongji Hospital,Huazhong University of Science and Technology,Wuhan,Hubei 430030,China [2]Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH 44106, USA [3]Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA [4]Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), Hubei University of Medicine, Shiyan, Hubei 442000, China [5]Department of Rheumatology, Jiangxi Provincial People’s Hospital, Nanchang, Jiangxi 330006, China [6]Institute of Allergy and Clinical Immunology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei 430030,China [7]Key Laboratory of Vascular Aging (HUST), Ministry of Education, Wuhan, Hubei 430030, China

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Multiple sclerosis (MS) has been considered as a T cell-mediated autoimmune disease. However, the signaling pathways regulating effector T cells in MS have yet to be elucidated. Janus kinase 2 (JAK2) plays a crucial role in hematopoietic/immune cytokine receptor signal transduction. Here, we tested the mechanistic regulation of JAK2 and the therapeutic potential of pharmacological JAK2 inhibition in MS. Both inducible whole-body JAK2 knockout and T cell-specific JAK2 knockout completely prevented the onset of experimental autoimmune encephalomyelitis (EAE), a widely used MS animal model. Mice with JAK2 deficiency in T cells exhibited minimal demyelination and minimal CD45+ leukocyte infiltration in the spinal cord, accompanied by a remarkable reduction of T helper cell type 1 (TH1) and type 17 (TH17) in the draining lymph nodes and spinal cord. In vitro experiments showed that disruption of JAK2 markedly suppressed TH1 differentiation and IFNγ production. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was reduced in JAK2 deficient T cells, while STAT5 overexpression significantly increased TH1 and IFNγ production in STAT5 transgenic mice. Consistent with these results, JAK1/2 inhibitor baricitinib or selective JAK2 inhibitor fedratinib attenuated the frequencies of TH1 as well as TH17 in the draining lymph nodes and alleviated the EAE disease activity in mice. Our findings suggest that overactive JAK2 signaling in T lymphocytes is the culprit in EAE, which may serve as a potent therapeutic target for autoimmune disease.Copyright © 2023 Elsevier B.V. All rights reserved.

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出版当年[2022]版：

大类 | 2 区医学

小类 | 2 区免疫学 2 区药学

最新[2025]版：

大类 | 2 区医学

小类 | 2 区药学 3 区免疫学

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出版当年[2021]版：

Q1 PHARMACOLOGY & PHARMACY Q2 IMMUNOLOGY

最新[2023]版：

Q1 PHARMACOLOGY & PHARMACY Q2 IMMUNOLOGY

影响因子： 4.8 最新[2023版] 5 最新五年平均 5.714 出版当年[2021版] 5.597 出版当年五年平均 4.932 出版前一年[2020版] 5.6 出版后一年[2022版]

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第一作者单位： [1]Department of Rheumatology and Immunology,Tongji Hospital,Huazhong University of Science and Technology,Wuhan,Hubei 430030,China [2]Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH 44106, USA

通讯作者：

通讯机构： [1]Department of Rheumatology and Immunology,Tongji Hospital,Huazhong University of Science and Technology,Wuhan,Hubei 430030,China [2]Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH 44106, USA [5]Department of Rheumatology, Jiangxi Provincial People’s Hospital, Nanchang, Jiangxi 330006, China [6]Institute of Allergy and Clinical Immunology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei 430030,China [7]Key Laboratory of Vascular Aging (HUST), Ministry of Education, Wuhan, Hubei 430030, China [*1]Department of Rheumatology and Immunology,Tongji Hospital,Huazhong University of Science and Technology,Wuhan,Hubei 430030,China [*2]Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH 44106, USA

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