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DNA from macrophages induces fibrosis and vasculopathy through POLR3A/STING/type I interferon axis in systemic

Chaofan Liu1, Jiaxuan Tang1, Wei Luo2

  • 1Department of Dermatology.

Rheumatology (Oxford, England)
|June 10, 2022
PubMed
Abstract

Insights

Scleroderma (SSc) involves increased DNA leakage and activation of the STING pathway. Blocking this pathway offers a potential new treatment for SSc by targeting RNA polymerase III A (POLR3A).

Area of Science:

  • Immunology
  • Rheumatology
  • Molecular Biology

Background:

  • Scleroderma (SSc) pathogenesis involves complex molecular pathways.
  • The role of RNA polymerase III A (POLR3A) and type I Interferon (IFN) in SSc requires further clarification.
  • The stimulator of IFN genes (STING) pathway is implicated in inflammatory and autoimmune conditions.

Purpose of the Study:

  • To elucidate the function of POLR3A and type I IFN in SSc development.
  • To investigate the activation and role of the cytosolic DNA-STING pathway in SSc.
  • To evaluate the therapeutic potential of targeting the POLR3A/STING axis in SSc.

Main Methods:

  • Detection of cytosolic DNA and STING pathway markers in SSc patient samples (skin, serum) using immunofluorescence, immunohistochemistry, and western blotting.
  • In vitro experiments involving DNA transfection into SSc fibroblasts and human umbilical vein endothelial cells (HUVECs), followed by analysis of POLR3A/STING pathway activation.
  • Assessment of therapeutic interventions (H151 treatment, POLR3A/STING knockdown/knockout) on cellular responses and in a bleomycin-induced SSc mouse model.

Main Results:

  • Increased cytosolic DNA and STING pathway activation were observed in SSc patients.
  • Macrophage-derived DNA activated the POLR3A/STING/type I IFN pathway in fibroblasts and HUVECs, leading to monocyte adhesion and MCP-1 expression.
  • STING deficiency or H151 treatment ameliorated fibrosis and vasculopathy in vitro and in vivo.

Conclusions:

  • SSc is characterized by elevated DNA leakage and activation of the STING pathway.
  • The POLR3A/STING pathway mediates the induction of type I IFN signatures in fibroblasts and endothelial cells via macrophage-derived DNA.
  • Inhibition of the POLR3A/STING axis presents a promising therapeutic strategy for SSc.
Keywords:
RNA polymerase III ASScSTINGcytosolic DNAendothelial cellfibroblastfibrosistype I interferonvasculopathy

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