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. Author manuscript; available in PMC: 2019 Mar 1.
Published in final edited form as: Hepatology. 2018 Jan 24;67(3):1041–1055. doi: 10.1002/hep.29593

Figure 8. Schematic illustration of myeloid Notch1 signaling in the regulation of innate immune response in IR-triggered liver inflammation.

Figure 8

Notch1 can be activated in IR-stressed livers. Upon ligand binding, Notch1 is cleaved by γ-secretase leading to a release of the intracellular domain (NICD), which translocates into the nucleus and forms a complex with the CSL DNA-binding protein and activates its target gene Hes1. Induction of Hes1 inhibits JNK binding protein JSAP1-mediated ROCK1 activation. Blockade of ROCK1 reduces PTEN and augments Akt activity, leading to suppressed TLR4 signaling in liver IRI. In addition, the Notch-Hes1 axis inhibits JSAP1-dependent ROCK1 and caspase-3 activity, resulting in reduced hepatocellular apoptosis/necrosis in IR-triggered liver inflammation.