Biology subjects

De Nardo, D.

Publications and source records attributed to De Nardo, D..

2 recordsLinked to original sources

bioRxiv2020

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

Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor (TLR)-4 expressed on macrophages induces a robust pro-inflammatory response which has recently been shown to be dependent on metabolic reprogramming 1, 2, 3, 4. These innate metabolic changes have been compared to the Warburg effect (also known as aerobic glycolysis) described in tumour cells 5, 6. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming remain 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 both ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, the production of the central immune-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.

immunology↗

bioRxiv2019

IRAK1-mediated coincidence detection of microbial signals licenses inflammasome activation

The innate immune system signals through various higher order signaling complexes called supramolecular organizing centers (SMOCs), which typically organize components of a single pathway. While innate immune signaling pathways have been largely characterized using single receptor stimuli, responses to pathogens require the coordinated engagement of multiple pathways. Here, we report an IRAK1-containing SMOC formed specifically when multiple receptors are activated, which recruits select components of the TLR, MAPK and inflammasome pathways. This allows for signal flux redistribution from TLRs to inflammasomes and facilitates inflammasome licensing through an MKK7-JNK axis, which is defective in Irak1-/- mice. Furthermore, this defect in Irak1-/- mice manifests in increased susceptibility to inflammasome-sensitive pathogens and diminished IL1 production from inflammasomes after co-TLR priming. Thus, IRAK1 SMOCs form a multi-pathway coordinating hub for coincidence detection of microbial signals, which may be employed by innate immune cells as a threat assessment and thresholding mechanism for inflammasome activation.

immunology↗