Dataset Information

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

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

Luo Huqiao H Urbonaviciute Vilma V Saei Amir Ata AA Lyu Hezheng H Gaetani Massimiliano M Végvári Ákos Á Li Yanpeng Y Zubarev Roman A RA Holmdahl Rikard R

JCI insight 20230410 7

Low capacity to produce ROS because of mutations in neutrophil cytosolic factor 1 (NCF1/p47phox), a component of NADPH oxidase 2 (NOX2) complex, is strongly associated with systemic lupus erythematosus in both humans and mouse models. Here, we aimed to identify the key immune cell type(s) and cellular mechanisms driving lupus pathogenesis under the condition of NCF1-dependent ROS deficiency. Using cell-specific Cre-deleter, human NCF1-339 variant knockin, and transgenic mouse strains, we show th ...[more]

PMID: 36853827

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