Interleukin-1β Signaling in Dendritic Cells Induces Antiviral Interferon Responses.

Lauren D Aarreberg,Michael Gale,Kwan Chow,Michael A Davis,Hilario J Ramos,Richard Green,Courtney Wilkins,Stacey Schultz-Cherry

doi:10.1128/mbio.00342-18

Abstract

ABSTRACTInduction of interferon beta (IFN-β), IFN-stimulated genes (ISGs), and inflammatory responses is critical for control of viral infection. We recently identified an essential linkage of stimulation of the inflammatory cytokine interleukin-1β (IL-1β) and induction of ISGs that function as host restriction pathways against the emerging flavivirus West Nile virus (WNV) in vivo. Here we utilized ex vivo global transcriptome analysis of primary dendritic cells, known targets of WNV replication, to define gene signatures required for this IL-1β-driven antiviral response. Dendritic cells that were deficient in IL-1 receptor signaling showed dysregulation of cell-intrinsic defense genes and loss of viral control during WNV infection. Surprisingly, we found that in wild-type cells, IL-1β treatment, in the absence of infection, drove the transcription of IFN-β and ISGs at late times following treatment. Expression of these antiviral innate immune genes was dependent on the transcription factor IFN regulatory factor 3 (IRF3) and appears to reflect a general shift in IL-1β signaling from an early inflammatory response to a late IFN-mediated response. These data demonstrate that inflammatory and antiviral signals integrate to control viral infection in myeloid cells through a process of IL-1β-to-IRF3 signaling crosstalk. Strategies to exploit these cytokines in the activation of host defense programs should be investigated as novel therapeutic approaches against individual pathogens.

Highlights

Induction of interferon beta (IFN-␤), IFN-stimulated genes (ISGs), and inflammatory responses is critical for control of viral infection
West Nile virus (WNV) replicated to similar titers in both WT and Il-1rϪ/Ϫ bone marrow-derived DCs (BMDCs) (Fig. 1A) and bone marrow-derived macrophages (BMMs) (Fig. 1B) at 24 h postinfection (p.i.)
We found that the general IFN regulatory factor (IRF) binding site and the IFN regulatory factor 3 (IRF3)/7 binding site are enriched within the list of downregulated genes at 24 h after IL-1␤ treatment but the IRF motifs are remarkably enriched in the list of genes upregulated at 48 h after IL-1␤ treatment, consistent with IL-1␤ driving a distinct crosstalk toward an innate immune antiviral response at 48 h posttreatment

Summary

Introduction

Induction of interferon beta (IFN-␤), IFN-stimulated genes (ISGs), and inflammatory responses is critical for control of viral infection. We found that in wild-type cells, IL-1␤ treatment, in the absence of infection, drove the transcription of IFN-␤ and ISGs at late times following treatment Expression of these antiviral innate immune genes was dependent on the transcription factor IFN regulatory factor 3 (IRF3) and appears to reflect a general shift in IL-1␤ signaling from an early inflammatory response to a late IFN-mediated response. These data demonstrate that inflammatory and antiviral signals integrate to control viral infection in myeloid cells through a process of IL-1␤-to-IRF3 signaling crosstalk. The significance of our research is in defining how virus-induced inflammatory responses regulate critical antiviral immune programs for effective control of West Nile virus infection. While inflammatory cell recruitment and function are necessary for limiting WNV pathogenesis, inflammation must be tightly controlled to prevent inflammationmediated destruction of CNS tissue and disease [1, 17,18,19]

Methods

Results

Conclusion