Neutrophil extracellular traps exacerbate Th1-mediated autoimmune responses in rheumatoid arthritis by promoting DC maturation

Eur J Immunol. 2016 Nov;46(11):2542-2554. doi: 10.1002/eji.201646542. Epub 2016 Oct 5.

Abstract

Aberrant formation of neutrophil extracellular traps (NETs) is a key feature in rheumatoid arthritis (RA) and plays a pivotal role in disease pathogenesis. However, the mechanism through which NETs shape the autoimmune response in RA remains elusive. In this study, we demonstrate that inhibition of peptidylarginine deiminases activity in collagen-induced arthritis (CIA) mouse model significantly reduces NET formation, attenuates clinical disease activity, and prevents joint destruction. Importantly, peptidylarginine deiminase 4 blocking markedly reduces the frequency of collagen-specific IFN-γ-producing T helper 1 (Th1) cells in the draining lymph nodes of immunized mice. Exposure of dendritic cells (DCs) to CIA-derived NETs induces DC maturation characterized by significant upregulation of costimulatory molecules, as well as elevated secretion of IL-6. Moreover, CIA-NET-treated DCs promote the induction of antigen-specific Th1 cells in vitro. Finally, NETs from RA patients show an increased potential to induce the maturation of DCs from healthy individuals, corroborating the findings obtained in CIA mouse model. Collectively, our findings delineate an important role of NETs in the induction and expansion of Th1 pathogenic cells in CIA through maturation of DCs and reveal a novel role of NETs in shaping the RA-autoimmune response that could be exploited therapeutically.

Keywords: Autoimmune responses; Cl-amidine; Collagen-induced arthritis; Neutrophil extracellular traps; Rheumatoid arthritis.

MeSH terms

  • Animals
  • Arthritis, Experimental / immunology
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / physiopathology
  • Autoimmunity*
  • Cell Differentiation / immunology*
  • Collagen / administration & dosage
  • Collagen / immunology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Extracellular Traps / drug effects
  • Extracellular Traps / immunology*
  • Humans
  • Hydrolases / metabolism
  • Interferon-gamma / metabolism
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Inbred DBA
  • Ornithine / administration & dosage
  • Ornithine / analogs & derivatives
  • Protein-Arginine Deiminase Type 4
  • Th1 Cells / immunology*

Substances

  • Interleukin-6
  • N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide
  • interleukin-6, mouse
  • Interferon-gamma
  • Collagen
  • Ornithine
  • Hydrolases
  • Protein-Arginine Deiminase Type 4
  • peptidylarginine deiminase 4, mouse