TGFβ regulates persistent neuroinflammation by controlling Th1 polarization and ROS production via monocyte-derived dendritic cells.
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.
['Parsa|Roham|R|', 'Lund|Harald|H|', 'Tosevski|Ivana|I|', 'Zhang|Xing-Mei|XM|', 'Malipiero|Ursula|U|', 'Beckervordersandforth|Jan|J|', 'Merkler|Doron|D|', 'Prinz|Marco|M|', 'Gyllenberg|Alexandra|A|', 'James|Tojo|T|', 'Warnecke|Andreas|A|', 'Hillert|Jan|J|', 'Alfredsson|Lars|L|', 'Kockum|Ingrid|I|', 'Olsson|Tomas|T|', 'Fontana|Adriano|A|', 'Suter|Tobias|T|', 'Harris|Robert A|RA|']
D000690:Amyotrophic Lateral Sclerosis D000818:Animals D016764:Cell Polarity D015331:Cohort Studies D016207:Cytokines D003713:Dendritic Cells D004195:Disease Models, Animal D004681:Encephalomyelitis, Autoimmune, Experimental D005786:Gene Expression Regulation D005838:Genotype D006801:Humans D017493:Leukocyte Common Antigens D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009000:Monocytes D063308:Myelin-Oligodendrocyte Glycoprotein D000074662:NADPH Oxidase 2 D020641:Polymorphism, Single Nucleotide D017382:Reactive Oxygen Species D018417:Th1 Cells D016212:Transforming Growth Factor beta
TGFβ monocyte-derived dendritic cells reactive oxygen species MOG-EAE gene deletion