Upregulation of H3K27 Demethylase KDM6 During Respiratory Syncytial Virus Infection Enhances Proinflammatory Responses and Immunopathology

Abstract

Severe disease following respiratory syncytial virus (RSV) infection has been linked to enhanced proinflammatory cytokine production that promotes a Th2-type immune environment. Epigenetic regulation in immune cells following viral infection plays a role in the inflammatory response and may result from upregulation of key epigenetic modifiers. In this study, we show that RSV-infected bone marrow-derived dendritic cells (BMDC) as well as pulmonary dendritic cells (DC) from RSV-infected mice upregulated the expression of Kdm6b/Jmjd3 and Kdm6a/Utx, H3K27 demethylases. KDM6-specific chemical inhibition (GSK J4) in BMDC led to decreased production of chemokines and cytokines associated with the inflammatory response during RSV infection (i.e., CCL-2, CCL-3, CCL-5, IL-6) as well as decreased MHC class II and costimulatory marker (CD80/86) expression. RSV-infected BMDC treated with GSK J4 altered coactivation of T cell cytokine production to RSV as well as a primary OVA response. Airway sensitization of naive mice with RSV-infected BMDCs exacerbate a live challenge with RSV infection but was inhibited when BMDCs were treated with GSK J4 prior to sensitization. Finally, in vivo treatment with the KDM6 inhibitor, GSK J4, during RSV infection reduced inflammatory DC in the lungs along with IL-13 levels and overall inflammation. These results suggest that KDM6 expression in DC enhances proinflammatory innate cytokine production to promote an altered Th2 immune response following RSV infection that leads to more severe immunopathology.

Uric acid pathway activation during respiratory virus infection promotes Th2 immune response via innate cytokine production and ILC2 accumulation

“…The coordinated production of innate cytokines from these different cell populations may further amplify the response since they exacerbate different pathways and together enhance ILC2 and inflammatory DC accumulation, activation that likely drive RSV-induced pathology. These findings are consistent with previous studies examining cell-specific expression of TSLP, IL-33 and CCL2 39 , 43 – 47 that leads to Th2 immune responses by subsequent ILC2 activation 9 , 14 , 48 . Here we extend these findings to suggest a pathway by which RSV can trigger the expression of these innate cytokines by uric acid-mediated mechanisms likely through the upregulation of purine metabolism.…”

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

“…Although not further investigated in our study, we demonstrate that KDM6 inhibition regulates Th1 and Th2 proinflammatory function, supporting a role for KDM6A/B enzymes in immune pathologies, including allergic and respiratory diseases (27,51). Although H3K27 demethylases KDM6A and KDM6B are constitutively expressed, the cytokine-induced and inflammatory stimulus (such as IL-4, IFN-γ, LPS, and thioglycolate)-induced temporal surge of KDM6B expression in immune cells, including macrophages (52,53), CD4 + T cells (27), dendritic cells (51), and neutrophils (54), suggests an important epigenetic mechanism in inflammatory scenarios by regulating an early adaptation or response to an inflammatory environment. Our study provides clear evidence that both KDM6 enzymes in humans are important regulatory elements of Th17 cells, by involvement in differentiation of Th17 cells, and in addition by controlling proliferation and proinflammatory effector functions of mature Th17 cells.…”

Biomarkers for diagnosis and prediction of therapy responses in allergic diseases and asthma

“…Infections such as RSV can even further shunt antiviral responses toward a more Type 2-centric response. [124][125][126][127][128] In addition, the discovery of ILC2s, a group of lymphoid cells, further emphasized the role of epithelial alarmins IL-25, IL-33 and TSLP in viral-induced exacerbation. 129 During viral infection, these three cytokines were secreted in response to epithelial injury.…”