Proceedings of the National Academy of Sciences - PNAS, 2012-03, Vol.109 (13), p.5004-5009
2012
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- Autor(en) / Beteiligte
- Titel
- Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2012-03, Vol.109 (13), p.5004-5009
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Suppressor of cytokine signaling (SOCS) proteins are feedback inhibitors of the JAK/STAT pathway. SOCS3 has a crucial role in inhibiting STAT3 activation, cytokine signaling, and inflammatory gene expression in macrophages/microglia. To determine the role of SOCS3 in myeloid cells in neuroinflammation, mice with conditional SOCS3 deletion in myeloid cells (LysMCre-SOCS3fl/fl) were tested for experimental autoimmune encephalomyelitis (EAE). The myeloid-specific SOCS3-deficient mice are vulnerable to myelin oligodendrocyte glycoprotein (MOG)-induced EAE, with a severe, nonresolving atypical form of disease. In vivo, enhanced infiltration of inflammatory cells and demyelination is prominent in the cerebellum of myeloid-specific SOCS3-deficient mice, as is enhanced STAT3 signaling and expression of inflammatory cytokines/chemokines and an immune response dominated by Th1 and Th17 cells. In vitro, SOCS3-deficient macrophages exhibit heightened STAT3 activation and are polarized toward the classical M1 phenotype. SOCS3-deficient M1 macrophages provide the microenvironment to polarize Th1 and Th17 cells and induce neuronal death. Furthermore, adoptive transfer of M2 macrophages into myeloid SOCS3-deficient mice leads to delayed onset and reduced severity of atypical EAE by decreasing STAT3 activation, Th1/Th17 cells, and proinflammatory mediators in the cerebellum. These findings indicate that myeloid cell SOCS3 provides protection from EAE through deactivation of neuroinflammatory responses.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1117218109Titel-ID: cdi_pnas_primary_109_13_5004
- Format
- –
- Schlagworte
- Adoptive transfer, Animals, Biological Sciences, Cell activation, Cell Count, Cell Polarity, Central nervous system, Cerebellum, Chemokines, Clonal deletion, Cytokines, Cytoprotection, Deactivation, death, Demyelination, encephalitis, Encephalomyelitis, Autoimmune, Experimental - complications, Encephalomyelitis, Autoimmune, Experimental - immunology, Encephalomyelitis, Autoimmune, Experimental - metabolism, Encephalomyelitis, Autoimmune, Experimental - pathology, Experimental allergic encephalomyelitis, Feedback, Gene Deletion, Gene expression, Glycoproteins, Helper cells, Immune response, Inflammation, Inflammation - complications, Inflammation - immunology, Inflammation - metabolism, Inflammation - pathology, Integrases - metabolism, Lymphocytes T, Macrophages, Macrophages - metabolism, Macrophages - pathology, Messenger RNA, Mice, Mice, Inbred C57BL, Microenvironments, Microglia, Myelin Proteins - immunology, myelin sheath, Myelin-Oligodendrocyte Glycoprotein, Myeloid cells, Myeloid Cells - immunology, Myeloid Cells - metabolism, Nervous System - immunology, Nervous System - metabolism, Nervous System - pathology, Nervous system diseases, neuroglia, Neurology, Neurons - metabolism, Neurons - pathology, Oligodendrocyte-myelin glycoprotein, Phenotype, Phenotypes, Rodents, Signal transduction, Signal Transduction - immunology, Stat3 protein, STAT3 Transcription Factor - metabolism, Suppressor of Cytokine Signaling 3 Protein, Suppressor of Cytokine Signaling Proteins - metabolism, T lymphocytes, Th1 Cells - cytology, Th1 Cells - immunology, Th17 Cells - cytology, Th17 Cells - immunology, Transcription