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

PLoS Pathogens

Mareike Albert¹  Kristian Helin¹  Steven L. Kunkel²  Sumanta Mukherjee²  Catherine Ptaschinski²  Nicholas W. Lukacs²  Martin L. Moore³ 

[1] Biotech Research and Innovation Centre, Centre for Epigenetics, and Danish Stem Cell Center, University of Copenhagen, Copenhagen, Denmark;Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America;Department of Pediatrics, Emory University, and Children’s Healthcare of Atlanta, Atlanta, Georgia, United States of America

关键词: Cytokines;    Small interfering RNAs;    T cells;    Mucus;    Epigenetics;    Immune response;    RNA extraction;    Respiratory infections;   

DOI  :  10.1371/journal.ppat.1004978

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 Kdm5bfl/fl-CD11c-Cre+ mice recapitulated the latter results during in vitro DC activation showing innate cytokine modulation. In vivo, infection of Kdm5bfl/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 Kdm5bfl/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.

【 授权许可】

CC BY