STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression

Jesse J. Balic, Hassan Albargy, Kevin Luu, Francis J. Kirby, W. Samantha N. Jayasekara, Finbar Mansell, Daniel J. Garama, Dominic Nardo, Nikola Baschuk, Cynthia Louis, Fiachra Humphries, Katherine Fitzgerald, Eicke Latz, Daniel J. Gough () and Ashley Mansell ()
Additional contact information
Jesse J. Balic: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
Hassan Albargy: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
Kevin Luu: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
Francis J. Kirby: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
W. Samantha N. Jayasekara: Monash University
Finbar Mansell: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
Daniel J. Garama: Monash University
Dominic Nardo: Monash University
Nikola Baschuk: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
Cynthia Louis: The Walter and Eliza Hall Institute of Medical Research
Fiachra Humphries: University of Massachusetts Medical School
Katherine Fitzgerald: University of Massachusetts Medical School
Eicke Latz: University Hospital Bonn, University of Bonn
Daniel J. Gough: Monash University
Ashley Mansell: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) on macrophages induces a robust pro-inflammatory response that is dependent on metabolic reprogramming. These innate metabolic changes have been compared to aerobic glycolysis in tumour cells. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming are unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, production of the central immune response metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.

Date: 2020
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DOI: 10.1038/s41467-020-17669-5

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