A stimulus‐contingent positive feedback loop enables IFN‐β dose‐dependent activation of pro‐inflammatory genes

• DOI: 10.15252/msb.202211294
• Publication Date: 2023-03-17T12:24:36Z
• Authors: Catera L Wilder; Diane Lefaudeux; Raisa Mathenge; Kensei Kishimoto; Alma Zuniga Munoz; Minh A Nguyen; Aaron S Meyer; Quen J Cheng; Alexander Hoffmann
• Keywords: 0301 basic medicine; Medicine (General); Bioinformatics; QH301-705.5; 1.1 Normal biological development and functioning; 610; stimulus‐contingent positive feedback loop; Antiviral Agents; Feedback; 03 medical and health sciences; R5-920; Genetics; Biology (General); IFN‐β; IFN-β; Inflammatory and immune system; 500; IFN-beta; inflammatory response; Articles; Biological Sciences; 3. Good health; Gene Expression Regulation; Biochemistry and cell biology; ISGF3; signaling dynamics; Biochemistry and Cell Biology; Other Biological Sciences; stimulus-contingent positive feedback loop; Transcription Factors; Signal Transduction

AbstractType I interferons (IFN) induce powerful antiviral and innate immune responses via the transcription factor, IFN‐stimulated gene factor (ISGF3). However, in some pathological contexts, type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN‐β also activates an inflammatory gene expression program in contrast to IFN‐λ3, a type III IFN, which elicits only the common antiviral gene program. We show that the inflammatory gene program depends on a second, potentiated phase in ISGF3 activation. Iterating between mathematical modeling and experimental analysis, we show that the ISGF3 activation network may engage a positive feedback loop with its subunits IRF9 and STAT2. This network motif mediates stimulus‐specific ISGF3 dynamics that are dependent on ligand, dose, and duration of exposure, and when engaged activates the inflammatory gene expression program. Our results reveal a previously underappreciated dynamical control of the JAK–STAT/IRF signaling network that may produce distinct biological responses and suggest that studies of type I IFN dysregulation, and in turn therapeutic remedies, may focus on feedback regulators within it.