title: ATF3 Is a Key Regulator of Macrophage IFN Responses.
abstract: Cytokines and IFNs downstream of innate immune pathways are critical for mounting an appropriate immune response to microbial infection. However, the expression of these inflammatory mediators is tightly regulated, as uncontrolled production can result in tissue damage and lead to chronic inflammatory conditions and autoimmune diseases. Activating transcription factor 3 (ATF3) is an important transcriptional modulator that limits the inflammatory response by controlling the expression of a number of cytokines and chemokines. However, its role in modulating IFN responses remains poorly defined. In this study, we demonstrate that ATF3 expression in macrophages is necessary for governing basal IFN-β expression, as well as the magnitude of IFN-β cytokine production following activation of innate immune receptors. We found that ATF3 acted as a transcriptional repressor and regulated IFN-β via direct binding to a previously unidentified specific regulatory site distal to the Ifnb1 promoter. Additionally, we observed that ATF3 itself is a type I IFN-inducible gene, and that ATF3 further modulates the expression of a subset of inflammatory genes downstream of IFN signaling, suggesting it constitutes a key component of an IFN negative feedback loop. Consistent with this, macrophages deficient in Atf3 showed enhanced viral clearance in lymphocytic choriomeningitis virus and vesicular stomatitis virus infection models. Our study therefore demonstrates an important role for ATF3 in modulating IFN responses in macrophages by controlling basal and inducible levels of IFNβ, as well as the expression of genes downstream of IFN signaling.
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Larisa I
authors.initials: LI
authors.lastname: Labzin
authors.affiliation: Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
authors.forename: Susanne V
authors.initials: SV
authors.lastname: Schmidt
authors.affiliation: Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
authors.forename: Marc
authors.initials: M
authors.lastname: Beyer
authors.affiliation: Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Krebs
authors.affiliation: Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klee
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Rainer
authors.initials: R
authors.lastname: Stahl
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; and German Center for Neurodegenerative Diseases, 53175 Bonn, Germany eicke.latz@uni-bonn.de denardo.d@wehi.edu.au.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia; eicke.latz@uni-bonn.de denardo.d@wehi.edu.au.
authors.forename: Dominic
authors.initials: D
authors.lastname: De Nardo
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D016899:Interferon-beta / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics*
chemical_list: D051700:Activating Transcription Factor 3; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta