Regulation of interferon and Toll‐like receptor signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms
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Summary: Activated macrophages and their inflammatory products play a key role in innate immunity and in pathogenesis of autoimmune/inflammatory diseases. Macrophage activation needs to be tightly regulated to rapidly mount responses to infectious challenges but to avoid toxicity associated with excessive activation. Rapid and potent macrophage activation is driven by cytokine‐mediated feedforward loops, while excessive activation is prevented by feedback inhibition. Here we discuss feedforward mechanisms that augment macrophage responses to Toll‐like receptor (TLR) ligands and cytokines that are mediated by signal transducer and activator of transcription 1 (STAT1) and induced by interferon‐γ (IFN‐γ). IFN‐γ also drives full macrophage activation by inactivating feedback inhibitory mechanisms, such as those mediated by interleukin‐10 (IL‐10), and STAT3. Priming of macrophages with IFN‐γ reprograms cellular responses to other cytokines, such as type I IFNs and IL‐10, with a shift toward pro‐inflammatory STAT1‐dominated responses. Similar but partially distinct priming effects are induced by other cytokines that activate STAT1, including type I IFNs and IL‐27. We propose a model whereby opposing feedforward and feedback inhibition loops crossregulate each other to fine tune macrophage activation. In addition, we discuss how dysregulation of the balance between feedforward and feedback inhibitory mechanisms can contribute to the pathogenesis of autoimmune and inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus.
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Classically activated macrophages require a priming signal in the form of interferon IFN-γ.
“Classically activated macrophages require a priming signal in the form of interferon IFN-γ [189].”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [189]
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- Authors
- Hu, X., Chakravarty, S. D., & Ivashkiv, L. B.
- Affiliations
- Hospital for Special Surgery (US)
- NewYork–Presbyterian Hospital (US)
- Corresponding author
- Ivashkiv, Lionel B.
- Venue
- Immunological Reviews
- Publisher
- Wiley
- Published
- 2008-10-30
- Volume
- 226
- Issue
- 1
- Pages
- 41-56
- ISSN
- 0105-2896 (ISSN-L)
- 1600-065X
- PMC
- PMC2630590
- OpenAlex
- W2016430217
- Cited by
- 303
- References
- 119
- Citations by year
- 2026: 7 · 2025: 23 · 2024: 13 · 2023: 15 · 2022: 14 · 2021: 14 · 2020: 10 · 2019: 17 · 2018: 16 · 2017: 31 · 2016: 21 · 2015: 13 · 2014: 17 · 2013: 13 · 2012: 28
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Immunological Reviews (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2r01ai046712-26)
- National Institute of Allergy and Infectious Diseases (R01-AI046712, R01AI059636, R01AI044938)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050401, R01AR046713)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- macrophage activation, feed-forward loop, product inhibition, interferon-gamma, Toll-like receptor signaling, STAT1, STAT3, IL-10, type I interferon, IL-27, cytokine priming, innate immunity, autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, inflammation
- MeSH terms
- Animals, Humans, Interferons, Macrophage Activation, Signal Transduction, Interleukin-10, Feedback, Physiological, STAT1 Transcription Factor, STAT3 Transcription Factor, Toll-Like Receptors
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