Jagged1-mediated myeloid Notch1 signaling activates HSF1/Snail and controls NLRP3 inflammasome activation in liver inflammatory injury.
MouseIschaemia-reperfusionHepaticNotch1 floxed crossed with LysM-Cre to give myeloid-specific Notch1 knockout, with floxed littermate controlsIntravenous (JAG1 and siRNA with mannose-conjugated polymers; macrophages by tail vein)Recombinant JAG1 0.5 mg/kg; Snail or nonspecific siRNA 2 mg…JAG1 1 h before ischaemia; siRNA 4 h before ischaemia; macrophage adoptive tran…
Model: Warm hepatic ischaemia/reperfusion injury; atraumatic clip occluding arterial and portal venous supply to cephalad liver lobes for 90 minutes of ischaemia followed by 6 hours of reperfusion
JAG1 significantly reduced serum ALT and Suzuki histological injury scores in Notch1-proficient mice relative to PBS controls, with less oedema and sinusoidal congestion, lower myeloperoxidase and lower pro-inflammatory gene expression. Treated livers showed increased NICD, HSF1, Snail and TRX1 wit…
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