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Eosinophil-mediated suppression and Anti-IL-5 enhancement of plasmacytoid dendritic cell interferon responses in asthma

ABSTRACT: Blood plasmacytoid dendritic cells (pDCs) purified from anonymous donors were stimulated ex vivo with rhinovirus-16 (RV) in the presence or absence of eosinophil supernatants. Purified pDCs from 8 individuals with moderate-severe asthma, treated or not treated with anti-IL-5/5Rα therapy, were cultured with or without RV. Transcriptome analysis revealed global repression of pDC IFN response patterns by eosinophils, most notably in basal expression of interferon stimulated genes (ISGs). Increased RV-induced IFNα secretion and transcription as well as increased basal ISG expression was detected in pDCs from participants treated with anti-IL-5/5Rα therapy. Our findings highlight a novel mechanism through which T2 inflammation regulates pDC IFNα responses relevant to RV respiratory infections in the context of eosinophilic airway disease and suggest one potential mechanism through with eosinophil-depleting therapies may reduce the severity of RV illness.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171378 | GEO | 2022/01/01

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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Eosinophil-mediated suppression and Anti-IL-5 enhancement of plasmacytoid dendritic cell interferon responses in asthma

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