NCF1-dependent low production of reactive oxygen species in plasmacytoid dendritic cells exacerbates lupus

ABSTRACT: Low capacity to produce reactive oxygen species (ROS) due to mutations in neutrophil cytosolic factor 1 (NCF1/p47phox) is strongly associated with lupus development both in humans and mouse models. Here, we aim to identify the major mechanisms of the Ncf1-disease association. We found that plasmacytoid dendritic cells (pDCs), the most potent producers of type I IFNs, exacerbate pristane-induced lupus in ROS-defective Ncf1-mutant and human NCF1-339 variant carrying mice. ROS deficiency in mouse models with Ncf1 mutation or human NCF1-339 variant leads to enhanced pDC generation via the TLR7/AKT/mTOR pathway and accumulation at sites of inflammation, resulting in an increased IFNα secretion. The produced IFNα further stimulates the JAK1/STAT1 pathway, which we found is hyperreactive in ROS-deficient pDCs. This, in turn, leads to increased type I IFN signature and enhanced proinflammatory responses. Our discoveries explain the causative effect of dysfunctional Ncf1 and pathogenicity of pDCs in lupus.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Dendritic Cell, Bone Marrow

SUBMITTER: Amir Ata Saei  

LAB HEAD: Prof. Roman A.Zubarev

PROVIDER: PXD035964 | Pride | 2023-03-12

REPOSITORIES: Pride