Human plasmacytoid dendritic cells regulate IFN‐α production through activation‐induced splicing of IL‐18Rα. Issue 6 (28th August 2014)

• Record Type: Journal Article
• Authors: Chao, Yinxia; Kaliaperumal, Nivashini; Chretien, Anne‐Sophie; Tang, Suisheng; Lee, Bernett; Poidinger, Michael; Fairhurst, Anna‐Marie; Connolly, John E.
• Is Part Of: Journal of leukocyte biology. Volume 96:Issue 6(2014)
• Page Start: 1037
• Page End: 1046
• Publication Date: 2014-08-28
• Subjects: anti‐viral response -- innate immunity -- inflammation; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.2A0813-465RR
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : A novel IL‐18Rα isoform and activation‐induced splicing of IL‐18Rα down‐modulates IFNα production in human pDCs upon viral exposure. Abstract : IFN‐α production by pDCs regulates host protection against viruses and is implicated in autoimmune pathology. Human pDCs express high levels of IL‐18R, but little is known of its role in pDC function. We report that IL‐18R signaling negatively regulates IFN‐α production through activation‐induced splicing of IL‐18Rα in human pDCs. Our data reveal two distinct isoforms of IL‐18Rα in human pDCs: the known, full‐length receptor (IL‐18Rα1) and a novel, truncated variant (IL‐18Rα2), which functions as a molecular decoy that competitively inhibits the canonical IL‐18Rα1/IL‐18Rβ signaling pathway. Whereas NK cells and pDCs both express IL‐18Rα1, pDCs express significantly higher levels of IL‐18Rα2, resulting in differential responses of these populations to IL‐18. Flu exposure increases IL‐18Rα1 expression in pDCs, and the blocking of IL‐18R enhances pDC production of IFN‐α and IP‐10; thus, pDCs use activation‐induced splicing to regulate IFN‐α production in response to flu. These data demonstrate that IL‐18R modulates IFN‐α release by human pDCs and suggest that IL‐18R signaling may represent a promising therapeutic target.