Tetramerization of STAT5 promotes autoimmune-mediated neuroinflammation.

Autor:	Monaghan KL; Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506., Aesoph D; Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506.; Department of Computer Science and Electrical Engineering, West Virginia University, Morgantown, WV 26506., Ammer AG; Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506.; Microscope Imaging Facility, West Virginia University, Morgantown, WV 26506., Zheng W; Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506., Rahimpour S; Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506., Farris BY; Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506., Spinner CA; Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892., Li P; Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892., Lin JX; Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892., Yu ZX; Pathology Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892., Lazarevic V; Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892., Hu G; Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506.; Bioinformatics Core, West Virginia University, Morgantown, WV 26506., Leonard WJ; Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892; wjl@helix.nih.gov edwin.wan@hsc.wvu.edu., Wan ECK; Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506; wjl@helix.nih.gov edwin.wan@hsc.wvu.edu.; Department of Neuroscience, West Virginia University, Morgantown, WV 26506.; Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Dec 28; Vol. 118 (52).
DOI:	10.1073/pnas.2116256118
Abstrakt:	Signal tranducer and activator of transcription 5 (STAT5) plays a critical role in mediating cellular responses following cytokine stimulation. STAT proteins critically signal via the formation of dimers, but additionally, STAT tetramers serve key biological roles, and we previously reported their importance in T and natural killer (NK) cell biology. However, the role of STAT5 tetramerization in autoimmune-mediated neuroinflammation has not been investigated. Using the STAT5 tetramer-deficient Stat5a - Stat5b N-domain double knockin (DKI) mouse strain, we report here that STAT5 tetramers promote the pathogenesis of experimental autoimmune encephalomyelitis (EAE). The mild EAE phenotype observed in DKI mice correlates with the impaired extravasation of pathogenic T-helper 17 (Th17) cells and interactions between Th17 cells and monocyte-derived cells (MDCs) in the meninges. We further demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated STAT5 tetramerization regulates the production of CCL17 by MDCs. Importantly, CCL17 can partially restore the pathogenicity of DKI Th17 cells, and this is dependent on the activity of the integrin VLA-4. Thus, our study reveals a GM-CSF-STAT5 tetramer-CCL17 pathway in MDCs that promotes autoimmune neuroinflammation. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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