TGF beta Regulates Persistent Neuroinflammation by Controlling Th1 Polarization and ROS Production via Monocyte-Derived Dendritic Cells

Roham Parsa, Harald Lund, Ivana Tosevski, Xing-Mei Zhang, Ursula Malipiero, Jan Beckervordersandforth, Doron Merkler, Marco Prinz, Alexandra Gyllenberg, Tojo James, Andreas Warnecke, Jan Hillert, Lars Alfredsson, Ingrid Kockum, Tomas Olsson, Adriano Fontana, Tobias Suter, Robert A. Harris*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Intracerebral levels of Transforming Growth Factor beta (TGF?) rise rapidly during the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis (MS). We addressed the role of TGF? responsiveness in EAE by targeting the TGF? 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. TGF? 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-?, 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.? 2016 The Authors. Glia Published by
Original languageEnglish
Pages (from-to)1925-1937
Issue number11
Publication statusPublished - Nov 2016


  • TGF beta
  • gene deletion
  • reactive oxygen species
  • monocyte-derived dendritic cells

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