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Updated: Dec 13, 2025
11:44
A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
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STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression
Jesse J Balic1,2, Hassan Albargy1,2, Kevin Luu1,2
1Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, 3168, Australia.
Nature Communications
|August 1, 2020
Summary
Toll-like receptor 4 (TLR4) activation triggers metabolic changes in macrophages, crucial for inflammation. This study reveals that STAT3 phosphorylation is key to this reprogramming and inflammatory cytokine production.
Area of Science:
- Immunology
- Cellular Metabolism
- Molecular Biology
Background:
- Toll-like receptor 4 (TLR4) activation on macrophages initiates pro-inflammatory responses.
- This response is metabolically dependent, resembling aerobic glycolysis seen in cancer cells.
- The precise mechanisms linking TLR4 activation to metabolic reprogramming remain unclear.
Purpose of the Study:
- To elucidate the signaling pathways connecting TLR4 activation to macrophage metabolic reprogramming.
- To investigate the role of STAT3 phosphorylation in TLR4-mediated metabolic and inflammatory responses.
Main Methods:
- Utilized a genetically engineered mouse model lacking STAT3 Ser727 phosphorylation.
- Performed ex vivo and in vivo analyses of macrophage responses to lipopolysaccharide (LPS).
- Assessed glycolytic reprogramming, succinate production, and inflammatory cytokine levels.
Main Results:
- TLR4 activation triggers a signaling cascade involving TRAF6 and TBK-1.
- TBK-1-mediated phosphorylation of STAT3 on Ser727 is essential for LPS-induced glycolytic reprogramming.
- STAT3 Ser727 phosphorylation is critical for succinate production and inflammatory cytokine release.
Conclusions:
- Non-canonical STAT3 activation serves as a vital signaling link between TLR4 and macrophage metabolic reprogramming.
- This pathway is crucial for driving inflammation in response to microbial components like LPS.
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