Fumarates Improve Psoriasis and Multiple Sclerosis by Inducing Type II Dendritic Cells

J Exp Med. 2011 Oct 24;208(11):2291-303. doi: 10.1084/jem.20100977. Epub 2011 Oct 10.

Abstract

Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4-producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4-producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter. This interaction prevents IL-23p19 transcription without affecting IL-12p35, whereas STAT1 inactivation prevents IL-12p35 transcription without affecting IL-23p19. As a consequence, GSH depletion by small molecules such as fumarates induces type II DCs in mice and in humans that ameliorate inflammatory autoimmune diseases. This therapeutic approach improves Th1- and Th17-mediated autoimmune diseases such as psoriasis and MS by interfering with IL-12 and IL-23 production.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / immunology
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Female
  • Fumarates / immunology*
  • Fumarates / therapeutic use*
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Interleukin-12 / immunology
  • Interleukin-23 / immunology
  • Macrophages / immunology
  • Mice
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / immunology*
  • NIH 3T3 Cells
  • Promoter Regions, Genetic
  • Psoriasis / drug therapy*
  • Psoriasis / immunology*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Transcription Factor RelA / metabolism

Substances

  • Fumarates
  • Interleukin-23
  • Reactive Oxygen Species
  • Rela protein, mouse
  • Transcription Factor RelA
  • Interleukin-12
  • Heme Oxygenase-1