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TGFβ regulates persistent neuroinflammation by controlling Th1 polarization and ROS production via monocyte-derived dendritic cells.
- Source :
-
Glia [Glia] 2016 Nov; Vol. 64 (11), pp. 1925-37. Date of Electronic Publication: 2016 Aug 01. - Publication Year :
- 2016
-
Abstract
- Intracerebral levels of Transforming Growth Factor beta (TGFβ) rise rapidly during the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis (MS). We addressed the role of TGFβ responsiveness in EAE by targeting the TGFβ receptor in myeloid cells, determining that Tgfbr2 was specifically targeted in monocyte-derived dendritic cells (moDCs) but not in CNS resident microglia by using bone-marrow chimeric mice. TGFβ responsiveness in moDCs was necessary for the remission phase since LysM(Cre) Tgfbr2(fl/fl) mice developed a chronic form of EAE characterized by severe demyelination and extensive infiltration of activated moDCs in the CNS. Tgfbr2 deficiency resulted in increased moDC IL-12 secretion that skewed T cells to produce IFN-γ, which in turn enhanced the production of moDC-derived reactive oxygen species that promote oxidative damage and demyelination. We identified SNPs in the human NOX2 (CYBB) gene that associated with the severity of MS, and significantly increased CYBB expression was recorded in PBMCs from both MS patients and from MS severity risk allele rs72619425-A carrying individuals. We thus identify a novel myeloid cell-T cell activation loop active in the CNS during chronic disease that could be therapeutically targeted. GLIA 2016;64:1925-1937.<br /> (© 2016 The Authors. Glia Published by Wiley Periodicals, Inc.)
- Subjects :
- Amyotrophic Lateral Sclerosis genetics
Animals
Cell Polarity genetics
Cohort Studies
Cytokines genetics
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental genetics
Encephalomyelitis, Autoimmune, Experimental immunology
Encephalomyelitis, Autoimmune, Experimental pathology
Gene Expression Regulation genetics
Genotype
Humans
Leukocyte Common Antigens genetics
Leukocyte Common Antigens metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Monocytes cytology
Myelin-Oligodendrocyte Glycoprotein immunology
Myelin-Oligodendrocyte Glycoprotein toxicity
NADPH Oxidase 2 genetics
NADPH Oxidase 2 metabolism
Polymorphism, Single Nucleotide genetics
Transforming Growth Factor beta genetics
Amyotrophic Lateral Sclerosis pathology
Cell Polarity physiology
Cytokines metabolism
Dendritic Cells physiology
Reactive Oxygen Species metabolism
Th1 Cells physiology
Transforming Growth Factor beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-1136
- Volume :
- 64
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Glia
- Publication Type :
- Academic Journal
- Accession number :
- 27479807
- Full Text :
- https://doi.org/10.1002/glia.23033