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

Kimberly A. Dill-McFarland, Justin T. Schwartz, Hongfang Zhao, Baomei Shao, Patricia C. Fulkerson, Matthew C. Altman, Michelle A. Gill

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background: Virus-induced IFN-α secretion by plasmacytoid dendritic cells (pDCs) is negatively impacted by IgE and has been linked to asthma exacerbations. Eosinophils, another contributor to type 2 inflammation, are also associated with asthma severity. Objective: We sought to investigate the impact of eosinophils on pDC antiviral interferon responses and determine whether anti–IL-5/5Rα therapy enhances pDC antiviral function. Methods: Blood pDCs purified from anonymous donors were stimulated in vitro with rhinovirus (RV)-16 in the presence or absence of eosinophils/eosinophil supernatants. IFN-α was measured in supernatants and RNA collected for bulk RNA-sequencing. Next, purified pDCs from 8 individuals with moderate to severe asthma, treated or not treated with anti–IL-5/5Rα therapy, were cultured ex vivo with or without RV; IFN-α secretion and differential gene expression analysis were compared between groups. Results: Exposure to either eosinophils or eosinophil supernatants inhibited RV-induced pDC IFN-α secretion in a dose-dependent manner and did not impact pDC viability. Eosinophil-derived neurotoxin and TGF-β partially recapitulated pDC IFN-α inhibition. Transcriptome analysis revealed global repression of pDC interferon response patterns by eosinophils, most notably in basal expression of interferon-stimulated genes. Increased RV-induced IFN-α secretion and transcription as well as increased basal interferon-stimulated gene expression was detected in pDCs from participants treated with anti–IL-5/5Rα therapy. Conclusions: Our findings highlight a novel mechanism through which type 2 inflammation regulates pDC IFN-α responses relevant to RV respiratory infections in the context of eosinophilic airway disease, suggesting a potential mechanism through which eosinophil-depleting therapies may reduce severity of RV illnesses.

Original languageEnglish
Pages (from-to)666-675
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Volume150
Issue number3
DOIs
StatePublished - Sep 2022

Keywords

  • IFN-α
  • Plasmacytoid dendritic cells
  • antiviral response
  • anti–IL-5
  • asthma
  • eosinophils
  • rhinovirus

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