A stimulus‐contingent positive feedback loop enables IFN‐β dose‐dependent activation of pro‐inflammatory genes
Abstract Type 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 ac...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2023-03-01
|
| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/msb.202211294 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846171536171466752 |
|---|---|
| author | Catera L Wilder Diane Lefaudeux Raisa Mathenge Kensei Kishimoto Alma Zuniga Munoz Minh A Nguyen Aaron S Meyer Quen J Cheng Alexander Hoffmann |
| author_facet | Catera L Wilder Diane Lefaudeux Raisa Mathenge Kensei Kishimoto Alma Zuniga Munoz Minh A Nguyen Aaron S Meyer Quen J Cheng Alexander Hoffmann |
| author_sort | Catera L Wilder |
| collection | DOAJ |
| description | Abstract Type 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. |
| format | Article |
| id | doaj-art-a5383c65692343a1ac5b165b07e6e06b |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2023-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-a5383c65692343a1ac5b165b07e6e06b2024-11-10T12:48:24ZengSpringer NatureMolecular Systems Biology1744-42922023-03-0119511910.15252/msb.202211294A stimulus‐contingent positive feedback loop enables IFN‐β dose‐dependent activation of pro‐inflammatory genesCatera L Wilder0Diane Lefaudeux1Raisa Mathenge2Kensei Kishimoto3Alma Zuniga Munoz4Minh A Nguyen5Aaron S Meyer6Quen J Cheng7Alexander Hoffmann8Department of Microbiology, Immunology, and Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology, and Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology, and Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology, and Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology, and Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology, and Molecular Genetics, University of CaliforniaDepartment of Bioengineering, University of CaliforniaDepartment of Microbiology, Immunology, and Molecular Genetics, University of CaliforniaDepartment of Microbiology, Immunology, and Molecular Genetics, University of CaliforniaAbstract Type 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.https://doi.org/10.15252/msb.202211294IFN‐βinflammatory responseISGF3signaling dynamicsstimulus‐contingent positive feedback loop |
| spellingShingle | Catera L Wilder Diane Lefaudeux Raisa Mathenge Kensei Kishimoto Alma Zuniga Munoz Minh A Nguyen Aaron S Meyer Quen J Cheng Alexander Hoffmann A stimulus‐contingent positive feedback loop enables IFN‐β dose‐dependent activation of pro‐inflammatory genes Molecular Systems Biology IFN‐β inflammatory response ISGF3 signaling dynamics stimulus‐contingent positive feedback loop |
| title | A stimulus‐contingent positive feedback loop enables IFN‐β dose‐dependent activation of pro‐inflammatory genes |
| title_full | A stimulus‐contingent positive feedback loop enables IFN‐β dose‐dependent activation of pro‐inflammatory genes |
| title_fullStr | A stimulus‐contingent positive feedback loop enables IFN‐β dose‐dependent activation of pro‐inflammatory genes |
| title_full_unstemmed | A stimulus‐contingent positive feedback loop enables IFN‐β dose‐dependent activation of pro‐inflammatory genes |
| title_short | A stimulus‐contingent positive feedback loop enables IFN‐β dose‐dependent activation of pro‐inflammatory genes |
| title_sort | stimulus contingent positive feedback loop enables ifn β dose dependent activation of pro inflammatory genes |
| topic | IFN‐β inflammatory response ISGF3 signaling dynamics stimulus‐contingent positive feedback loop |
| url | https://doi.org/10.15252/msb.202211294 |
| work_keys_str_mv | AT cateralwilder astimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT dianelefaudeux astimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT raisamathenge astimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT kenseikishimoto astimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT almazunigamunoz astimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT minhanguyen astimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT aaronsmeyer astimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT quenjcheng astimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT alexanderhoffmann astimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT cateralwilder stimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT dianelefaudeux stimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT raisamathenge stimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT kenseikishimoto stimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT almazunigamunoz stimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT minhanguyen stimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT aaronsmeyer stimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT quenjcheng stimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes AT alexanderhoffmann stimuluscontingentpositivefeedbackloopenablesifnbdosedependentactivationofproinflammatorygenes |