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An IFN/STAT1/CYBB Axis Defines Protective Plasmacytoid DC to Neutrophil Crosstalk in Aspergillus fumigatus Infected mice.

ABSTRACT: Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate sterilizing immunity against inhaled molds by controlling the local expression of a subunit required for functional NADPH oxidase assembly and activity in the lung.

ORGANISM(S): Mus musculus

PROVIDER: GSE280229 | GEO | 2025/07/17

REPOSITORIES: GEO

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An IFN/STAT1/CYBB Axis Defines Protective Plasmacytoid DC to Neutrophil Crosstalk in Aspergillus fumigatus Infected mice.

Project description:Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate sterilizing immunity against inhaled molds by controlling the local expression of a subunit required for functional NADPH oxidase assembly and activity in the lung.

2025-07-17 | GSE280164 | GEO

Expression data from pDC infected with Aspergillus fumigatus

Project description:Plasmacytoid dendritic cells (pDCs) were initially considered as critical for innate immunity to viruses. However, our group has shown that pDCs bind to and inhibit the growth of Aspergillus fumigatus hyphae and that depletion of pDCs renders mice hypersusceptible to experimental aspergillosis. In this study, we examined pDC receptors responsible for hyphal recognition and downstream events in pDCs stimulated by A. fumigatus hyphae. Our data show that Dectin-2 but not Dectin-1 participates in hyphal recognition by pDCs and that Dectin-2 acts in cooperation with the FcRÎ³ chain to trigger signaling responses. In addition, using confocal and electron microscopy we demonstrated that the interaction between pDCs and A. fumigatus induced the formation of pDC extracellular traps (pETs) containing DNA and citrullinated histone H3. Thus, these structures closely resembled those of neutrophil extracellular traps (NETs). Microarray analysis of the pDC transcriptome upon A. fumigatus infection demonstrated up-regulated expression of genes previously associated with viral infections or apoptosis. Moreover, the abundant expression of type I Interferon-encoding genes seen in CpG-stimulated pDCs was absent in the pDCs infected with A. fumigatus hyphae. Thus, human pDCs directly recognize A. fumigatus hyphae via Dectin-2. This interaction leads to formation of pET and triggers a distinct pattern of pDC gene expression. The spectrum of changes in gene expression was examined in pDCs from 3 blood donors, 2 and 4h following incubation with hyphae. Comparative controls included unstimulated and CpG-stimulated pDCs.

2014-03-01 | E-GEOD-55467 | biostudies-arrayexpress

Expression data from pDC infected with Aspergillus fumigatus

Project description:Plasmacytoid dendritic cells (pDCs) were initially considered as critical for innate immunity to viruses. However, our group has shown that pDCs bind to and inhibit the growth of Aspergillus fumigatus hyphae and that depletion of pDCs renders mice hypersusceptible to experimental aspergillosis. In this study, we examined pDC receptors responsible for hyphal recognition and downstream events in pDCs stimulated by A. fumigatus hyphae. Our data show that Dectin-2 but not Dectin-1 participates in hyphal recognition by pDCs and that Dectin-2 acts in cooperation with the FcRγ chain to trigger signaling responses. In addition, using confocal and electron microscopy we demonstrated that the interaction between pDCs and A. fumigatus induced the formation of pDC extracellular traps (pETs) containing DNA and citrullinated histone H3. Thus, these structures closely resembled those of neutrophil extracellular traps (NETs). Microarray analysis of the pDC transcriptome upon A. fumigatus infection demonstrated up-regulated expression of genes previously associated with viral infections or apoptosis. Moreover, the abundant expression of type I Interferon-encoding genes seen in CpG-stimulated pDCs was absent in the pDCs infected with A. fumigatus hyphae. Thus, human pDCs directly recognize A. fumigatus hyphae via Dectin-2. This interaction leads to formation of pET and triggers a distinct pattern of pDC gene expression.

2014-03-01 | GSE55467 | GEO

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

Project description: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.

2023-03-12 | PXD035964 | Pride

CITE-seq analysis of Mycobacterium tuberculosis infected B6 and Sp140-deficient mouse lungs

Project description:Mycobacterium tuberculosis (Mtb) causes 1.5 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the underlying cellular mechanisms remain poorly understood. We found that interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN during Mtb infection in mice and non-human primates, and pDCs localize near human Mtb granulomas. Depletion of pDCs reduces Mtb burdens, implicating pDCs in tuberculosis pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) known to activate pDCs. Single cell RNA-seq indicates that type I IFNs act on IMs to impair their responses to IFNg, a cytokine critical for Mtb control. Cell type-specific disruption of the type I IFN receptor suggests IFNs act on IMs to inhibit Mtb control. We propose pDC-derived type I IFNs, driven by NETs, act on IMs to drive bacterial replication, further neutrophil recruitment, and active tuberculosis disease.

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Bulk RNA-seq analysis of Mycobacterium tuberculosis infected Sp140-sufficient and -deficient mouse lungs with and without pDC depletion

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Tissue-specific differentiation of a circulating CCR9- pDC-like common dendritic cell precursor

Project description:Committed precursors of conventional dendritic cells (pre-cDCs) derived from the common DC progenitor which differentiate into cDC subpopulations in peripheral tissues have been identified, but committed precursors for plasmacytoid DCs (pDCs) have not been found. Here we show that CDP-derived ‘CCR9- MHCIIlow BST2+ Siglec-H+ pDCs from murine bone marrow which enter the circulation and peripheral tissues have a common DC precursor function in vivo in the steady state. Upon adoptive transfer the fate of CCR9- pDC-like precursors is governed by the tissues they enter. In the bone marrow and liver most transferred CCR9- pDC-like precursors differentiate into CCR9+ pDCs, whereas in peripheral lymphoid organs, lung and intestine they can give rise to CCR9+ pDCs and cDCs. Thus, CCR9- pDC-like cells are novel CDP-derived circulating DC precursors with pDC and cDC potential, whose final differentiation depends on tissue-specific factors allowing adaptation to local requirements. Total RNA obtained from CCR9- pDC-like common DC progenitors and CCR9+ pDCs was compared for differential gene expression. 3 independent isolations were performed for the 2 samples. 6 arrays were run in total.

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IFNg Regulates NAD+ Metabolism in Human Monocytes

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2021-12-31 | GSE176562 | GEO

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