Myeloid Notch1 deficiency activates the RhoA/ROCK pathway and aggravates hepatocellular damage in mouse ischemic livers

• DOI: 10.1002/hep.29593
• Publication Date: 2017-10-12T16:28:40Z
• Authors: Ling Lu; Shi Yue; Longfeng Jiang; Changyong Li; Qiang Zhu; Michael Ke; Hao Lu; Xuehao Wang; Ronald W. Busuttil; Qi‐Long Ying; Jerzy W. Kupiec‐W...; Bibo Ke
• Keywords: HES1

Notch signaling plays an emerging role in the regulation of immune cell development and function during inflammatory response. Activation ras homolog gene family member A/Rho‐associated protein kinase (ROCK) pathway promotes leukocyte accumulation tissue injury. However, it remains unknown whether regulates A/ROCK–mediated responses liver ischemia reperfusion (IR) This study investigated intracellular pathways regulated by receptors IR‐stressed vitro . In a mouse model IR‐induced injury, we found that mice with myeloid‐specific Notch1 knockout showed aggravated hepatocellular damage, increased serum alanine aminotransferase levels, apoptosis, macrophage/neutrophil trafficking, proinflammatory mediators compared to Notch1‐proficient controls. Unlike controls, myeloid ablation diminished hairy enhancer split‐1 (Hes1) augmented c‐Jun N‐terminal (JNK)/stress‐activated kinase–associated 1 (JSAP1), JNK, ROCK1, phosphatase tensin (PTEN) activation ischemic livers. Disruption JSAP1 livers improved reduced PTEN, toll‐like receptor 4 activation. Moreover, ROCK1 knockdown inhibited PTEN promoted Akt, leading depressed 4. parallel studies, transfection lentivirus‐expressing domain Hes1 lipopolysaccharide‐stimulated bone marrow–derived macrophages. deletion enhanced JSAP1/JNK activation, whereas clustered regularly interspaced short palindromic repeats/CRISPR‐associated 9–mediated ROCK1/PTEN signaling. Conclusion: Myeloid deficiency activates A/ROCK exacerbates injury inhibiting transcriptional repressor inducing scaffold IR‐triggered inflammation; our findings underscore crucial Notch–Hes1 axis as novel regulator innate immunity‐mediated inflammation imply therapeutic potential for management organ IR transplant recipients. (H epatology 2018;67:1041–1055)