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NCF1-dependent production of ROS protects against lupus by regulating plasmacytoid dendritic cell development and

Huqiao Luo1, Vilma Urbonaviciute1, Amir Ata Saei2,3

  • 1Division of Medical Inflammation Research and.

JCI Insight
|February 28, 2023
PubMed

Insights

Mutations in neutrophil cytosolic factor 1 (NCF1) impair ROS production, worsening lupus. Restoring ROS in plasmacytoid dendritic cells (pDCs) protects against lupus by reducing pDC accumulation and type I interferon responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Mutations in neutrophil cytosolic factor 1 (NCF1/p47phox), a key component of the NADPH oxidase 2 (NOX2) complex, lead to reduced reactive oxygen species (ROS) production.
  • This deficiency in ROS is strongly linked to systemic lupus erythematosus (SLE) in both human patients and animal models.

Purpose of the Study:

  • To identify the specific immune cells and cellular mechanisms responsible for lupus pathogenesis when NCF1-dependent ROS production is compromised.
  • To investigate how impaired ROS production in specific cell types contributes to the development and exacerbation of lupus.

Main Methods:

  • Utilized cell-specific Cre-deleter, human NCF1-339 variant knockin, and transgenic mouse models.
  • Analyzed pDC accumulation, IFN-α levels, IFN-stimulated genes, AKT/mTOR pathway, CCR2-mediated migration, and the stimulator of interferon genes (STING)/IFN-α/JAK1/STAT1 cascade.
  • Restored NOX2-derived ROS specifically in pDCs to assess therapeutic effects.

Main Results:

  • Low ROS production in plasmacytoid dendritic cells (pDCs) exacerbated lupus in both pristane-induced and spontaneous models.
  • pDC accumulation in organs, elevated IFN-α, and increased IFN-stimulated genes were observed.
  • ROS deficiency enhanced pDC generation and migration via AKT/mTOR and CCR2 pathways, amplifying type I interferon responses through the STING/IFN-α/JAK1/STAT1 cascade.

Conclusions:

  • Dysfunctional NCF1 and subsequent ROS deficiency in pDCs are causative factors in lupus pathogenesis.
  • Restoring NOX2-derived ROS specifically in pDCs offers a protective effect against lupus.
  • pDC-derived ROS plays a crucial protective role in preventing NCF1-dependent ROS deficiency-driven lupus.
Keywords:
AutoimmunityDendritic cellsLupus

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