Interferon regulatory factor (IRF) 3 is critical for the development of experimental autoimmune encephalomyelitis

J Neuroinflammation. 2014 Jul 28:11:130. doi: 10.1186/1742-2094-11-130.

Abstract

Background: Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune inflammatory demyelination that is mediated by Th1 and Th17 cells. The transcription factor interferon regulatory factor 3 (IRF3) is activated by pathogen recognition receptors and induces interferon-β production.

Methods: To determine the role of IRF3 in autoimmune inflammation, we immunised wild-type (WT) and irf3(-/-) mice to induce EAE. Splenocytes from WT and irf3(-/-) mice were also activated in vitro in Th17-polarising conditions.

Results: Clinical signs of disease were significantly lower in mice lacking IRF3, with reduced Th1 and Th17 cells in the central nervous system. Peripheral T-cell responses were also diminished, including impaired proliferation and Th17 development in irf3(-/-) mice. Myelin-reactive CD4+ cells lacking IRF3 completely failed to transfer EAE in Th17-polarised models as did WT cells transferred into irf3(-/-) recipients. Furthermore, IRF3 deficiency in non-CD4+ cells conferred impairment of Th17 development in antigen-activated cultures.

Conclusion: These data show that IRF3 plays a crucial role in development of Th17 responses and EAE and warrants investigation in human multiple sclerosis.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / pathology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cytokines / metabolism
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Flow Cytometry
  • Interferon Regulatory Factor-3 / deficiency*
  • Interferon Regulatory Factor-3 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myelin-Oligodendrocyte Glycoprotein / toxicity
  • Peptide Fragments / toxicity
  • Phorbol Esters / pharmacology
  • Spinal Cord / pathology
  • T-Lymphocytes / drug effects
  • Th17 Cells / drug effects
  • Th17 Cells / metabolism
  • Transfection

Substances

  • Cytokines
  • Interferon Regulatory Factor-3
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Phorbol Esters
  • myelin oligodendrocyte glycoprotein (35-55)
  • phorbol-12,13-diacetate