Interferon-β Intensifies Interleukin-23-Driven Pathogenicity of T Helper Cells in Neuroinflammatory Disease

Cells. 2021 Aug 20;10(8):2139. doi: 10.3390/cells10082139.

Abstract

Interferon (IFN)-β is a popular therapy for multiple sclerosis (MS). However, 25-40% of patients are nonresponsive to this therapy, and it worsens neuromyelitis optica (NMO), another neuroinflammatory disease. We previously identified, in both NMO patients and in mice, that IFN-β treatment had inflammatory effects in T Helper (TH) 17-induced disease through the production of the inflammatory cytokine IL-6. However, other studies have shown that IFN-β inhibits the differentiation and function of TH17 cells. In this manuscript, we identified that IFN-β had differential effects on discrete stages of TH17 development. During early TH17 development, IFN-β inhibits IL-17 production. Conversely, during late TH17 differentiation, IFN-β synergizes with IL-23 to promote a pathogenic T cell that has both TH1 and TH17 characteristics and expresses elevated levels of the potent inflammatory cytokines IL-6 and GM-CSF and the transcription factor BLIMP. Together, these findings help resolve a paradox surrounding IFN-β and TH17-induced disease and illuminate the pathways responsible for the pathophysiology of NMO and MS patients who are IFN-β nonresponders.

Keywords: T helper 17; experimental autoimmune encephalomyelitis; interferon-beta.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Cell Differentiation / immunology
  • Cytokines / immunology
  • Cytokines / metabolism
  • Drug Synergism
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Interferon-beta / pharmacology*
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Interleukin-23 / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Th17 Cells / cytology
  • Th17 Cells / drug effects*
  • Th17 Cells / immunology
  • Transcription Factors / immunology
  • Transcription Factors / metabolism

Substances

  • Cytokines
  • Inflammation Mediators
  • Interleukin-17
  • Interleukin-23
  • Transcription Factors
  • Interferon-beta
  • Granulocyte-Macrophage Colony-Stimulating Factor