ATF3 Is a key regulator of macrophage IFN responses

Labzin, LI; Schmidt, SV; Masters, SL; Beyer, M; Krebs, W; Klee, K; Stahl, R; Lutjohann, D; Schultze, JL; Latz, E; De Nardo, D

Author(s): Labzin, LI; Schmidt, SV; Masters, SL; Beyer, M; Krebs, W; Klee, K; Stahl, R; Lutjohann, D; Schultze, JL; Latz, E; De Nardo, D;
Details: Publication Year 2015-09-28,Volume 195,Issue #9,Page 4446-55
Journal Title: Journal of Immunology
Publication Type: Journal Article
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-beta expression, as well as the magnitude of IFN-beta cytokine production following activation of innate immune receptors. We found that ATF3 acted as a transcriptional repressor and regulated IFN-beta 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 IFNbeta, as well as the expression of genes downstream of IFN signaling.
Publisher: ASI
Research Division(s): Inflammation
PubMed ID: 26416280
Publisher's Version: https://doi.org/10.4049/jimmunol.1500204
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2015-10-23 03:05:36

Last Modified: 2015-11-18 02:14:25