RSV-Induced H3K4 Demethylase KDM5B Leads to Regulation of Dendritic Cell-Derived Innate Cytokines and Exacerbates Pathogenesis In Vivo

• Type of Material: Article
• Authors: Catherine Ptaschinski, University of Michigan, Ann Arbor; Sumanta Mukherjee, University of Michigan, Ann Arbor; Martin Moore, Emory University; Mareike Albert, University of Copenhagen; Kristian Helin, University of Copenhagen; Steven L. Kunkel, University of Michigan, Ann Arbor; Nicholas W. Lukacs, University of Michigan, Ann Arbor
• Language: English
• Date: 2015-06-17
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Ptaschinski et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1004978
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 11
• Issue: 6
• Start Page: e1004978
• End Page: e1004978
• Grant/Funding Information: NWL is funded by the National Institutes of Health grant # RO1AI036302 (http://www.nih.gov).; KH is funded by the Danish National Research Foundation (http://dg.dk/en/).; KH is funded by the Danish Medical Research Council (http://ufm.dk/en/).; MA is funded by the European Molecular Biology Organization Long Term Postdoctoral Fellowship (http://www.embo.org).
• Keywords: US CHILDREN; BRONCHIOLITIS; BETA; Small interfering RNAs; INTERFERON RESPONSE; INFECTION; Cytokines; RNA extraction; IMMUNE-SYSTEM; Microbiology; EPITHELIAL-CELLS; EPIGENETIC SIGNATURE; Mucus; Virology; Immune response; Life Sciences & Biomedicine; Epigenetics; RESPIRATORY-SYNCYTIAL-VIRUS; Parasitology; T cells; Respiratory infections; PROTEIN; Science & Technology
• Research Categories: Health Sciences, Pathology; Biology, Virology; Health Sciences, Immunology

Abstract

Respiratory syncytial virus (RSV) infection can result in severe disease partially due to its ability to interfere with the initiation of Th1 responses targeting the production of type I interferons (IFN) and promoting a Th2 immune environment. Epigenetic modulation of gene transcription has been shown to be important in regulating inflammatory pathways. RSV-infected bone marrow-derived DCs (BMDCs) upregulated expression of Kdm5b/Jarid1b H3K4 demethylase. Kdm5b-specific siRNA inhibition in BMDC led to a 10-fold increase in IFN-β as well as increases in IL-6 and TNF-α compared to control-transfected cells. The generation of Kdm5b^fl/fl-CD11c-Cre⁺mice recapitulated the latter results during in vitro DC activation showing innate cytokine modulation. In vivo, infection of Kdm5b^fl/fl-CD11c-Cre⁺mice with RSV resulted in higher production of IFN-γ and reduced IL-4 and IL-5 compared to littermate controls, with significantly decreased inflammation, IL-13, and mucus production in the lungs. Sensitization with RSV-infected DCs into the airways of naïve mice led to an exacerbated response when mice were challenged with live RSV infection. When Kdm5b was blocked in DCs with siRNA or DCs from Kdm5b^fl/fl-CD11c-CRE mice were used, the exacerbated response was abrogated. Importantly, human monocyte-derived DCs treated with a chemical inhibitor for KDM5B resulted in increased innate cytokine levels as well as elicited decreased Th2 cytokines when co-cultured with RSV reactivated CD4⁺T cells. These results suggest that KDM5B acts to repress type I IFN and other innate cytokines to promote an altered immune response following RSV infection that contributes to development of chronic disease.