title: Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation.
abstract: 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-SOCS3(fl/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.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. hqin@uab.edu
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qin
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Yeh
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Sarno
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Holdbrooks
authors.forename: Yudong
authors.initials: Y
authors.lastname: Liu
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Muldowney
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Reynolds
authors.forename: Lora L
authors.initials: LL
authors.lastname: Yanagisawa
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fox
authors.forename: Keun
authors.initials: K
authors.lastname: Park
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Harrington
authors.forename: Chander
authors.initials: C
authors.lastname: Raman
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D000818:Animals; D002452:Cell Count; D016764:Cell Polarity; D019610:Cytoprotection; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D019426:Integrases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D009420:Nervous System / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology
chemical_list: C571327:Mog protein, mouse; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C045073:Cre recombinase; D019426:Integrases