Modulation of innate immune responses by ATF3 — ASN Events

Modulation of innate immune responses by ATF3 (#36)

Dominic De Nardo 1 , Larisa I Labzin 1 , Susanne Schmidt 2 , Seth L Masters 3 , Rainer Stahl 1 , Joachim Schultze 2 , Eicke Latz 1 4 5
  1. Institute of Innate Immunity, Bonn, Germany
  2. Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
  3. The Walter and Eliza Hall Institute (WEHI) for Medical Research, Parkville, VIC, Australia
  4. Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, USA
  5. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

Our body is continuously exposed to a diverse array of infectious agents, foreign antigens, and host-derived danger signals. The innate immune system plays a vital role as the first line of defence against these insults by protecting the host from infection and maintaining tissue homeostasis. Families of signalling receptors (e.g. TLRs) recognize invading microbes and co-ordinate an appropriate inflammatory response via the production of pro-inflammatory cytokines and type I interferons (IFNs) to clear infection. However, inappropriate activation of innate immune receptors and unregulated production of inflammatory mediators is thought to be the basis for many acute and chronic inflammatory conditions. Indeed, excessive IFN production is implicated in the pathogenesis of lupus and atherosclerosis. Maintaining a balance between the beneficial and detrimental effects of IFNs is therefore crucial and their production must be tightly regulated. Yet these precise regulatory mechanisms remain poorly understood. We have discovered that macrophages deficient in the transcriptional modulator, ATF3, display significantly greater IFNβ production following activation of TLRs and other innate immune receptors, as well as reduced LCMV viral infection. In contrast, overexpression of ATF3 in macrophages reduced the induction of IFNβ and increased viral replication. Utilizing a range of molecular biology, biochemical and immunological techniques, integrated with powerful bioinformatics approaches we have investigated the molecular mechanisms responsible for ATF3-mediated regulation of IFNβ. Our ATF3 ChIP-seq data has revealed that ATF3 regulates IFNβ by binding directly to its promoter. Furthermore, we have found that ATF3 itself is regulated by IFNs and thus forms part of a negative feedback loop during the induction of IFN signalling. Together our findings indicate ATF3 is a critical regulator of the IFN innate immune response. A better understanding of how the innate immune response is regulated is imperative for the development of future therapeutic strategies against autoimmune and inflammatory diseases.