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Plasmacytoid dendritic cells are dispensable or detrimental in murine systemic or respiratory viral infections [RNA-Seq 1]

ABSTRACT: Plasmacytoid dendritic cells (pDCs) are major producers of type I/III interferons. Since these cytokines are crucial for antiviral defense, it is assumed to be also the case for pDCs. However, robust evidence supporting this dogma is scarce. Genetic mutations or pharmacological manipulations causing pDC loss or disrupting their interferon production affect other immune cells, which could confound interpretation. To overcome this bottleneck, we engineered pDC-less mice, specifically and constitutively devoid of pDCs because expressing diphteria toxin under coordinated control by the Siglech and Pacsin1 genes co-expressed only in pDCs. pDC-less mice mounted protective intrinsic and innate immune responses against systemic infection with mouse cytomegalovirus, and were more resistant to intranasal infection with influenza virus and SARS-CoV2. Thus, contrary to dogma, pDCs and their interferon production proved dispensable or deleterious during systemic or respiratory viral infections. pDC-less mice will enable rigorously revisiting the roles of pDCs in health and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE302124 | GEO | 2025/09/19

REPOSITORIES: GEO

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Project description:To identify potential dysregulation of miRNA expression in plasmacytoid dendritic cells from Systemic Sclerosis patients (SSc), miRNA profiling was performed in pDCs from healthy donors or patients with the most severe fibrotic cutaneous form of SSc, namely in dcSSc, with either disease duration shorter (edcSSc) or longer than two years (ldcSSc). Plasmacytoid dendritic cells (pDCs) are a critical source of type I interferons (IFNs) that can contribute to the onset and maintenance of autoimmunity. Molecular mechanisms leading to pDC dysregulation and persistent type I IFN signature are largely unexplored, especially in systemic sclerosis (SSc), a disease in which pDCs infiltrate fibrotic skin lesions and produce higher levels of IFNa as compared to healthy controls. To investigate potential microRNA–mediated epigenetic mechanisms underlying pDC dysregulation and type I IFN production in SSc. microRNA expression profiling and validation was performed in highly purified pDCs obtained from the peripheral blood of 3 independent cohorts of healthy controls and SSc patients. Possible functions of miR-618 on pDC biology were identified by overexpression in healthy pDCs. miR-618 expression was upregulated in pDCs of SSc patients, including those in the early stage of disease onset and not presenting with skin fibrosis. IRF8, a crucial transcription factor for pDC development and activation, was identified as a target of miR-618. miR-618 overexpression reduced the development of pDCs from CD34+ cells in-vitro and enhanced their ability to secrete IFNα, mimicking the pDC phenotype observed in SSc patients. miR-618 upregulation suppresses pDC development and increases their ability to secrete IFNα, potentially contributing to the type I IFN signature observed in SSc patients. Considering the importance of pDCs in the pathogenesis of SSc and other diseases characterized by a type I IFN signature, miR-618 potentially represents an important epigenetic target to regulate immune system homeostasis in these conditions.

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Plasmacytoid dendritic cells are dispensable or detrimental in murine systemic or respiratory viral infections [RNA-Seq 1]

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