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Hepatology. 2019 May 7. doi: 10.1002/hep.30700. [Epub ahead of print]

Hippo signaling controls NLRP3 Activation and governs immunoregulation of mesenchymal stem cells in mouse liver injury.

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The Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.


The Hippo pathway, an evolutionarily conserved protein kinase cascade, tightly regulates cell growth and survival. Activation of yes-associated protein (YAP), a downstream effector of the Hippo pathway, has been shown to modulate tissue inflammation. However, it remains unknown as to whether and how the Hippo-YAP signaling may control NLRP3 activation in mesenchymal stem cell (MSC)-mediated immune regulation during liver inflammation. In a mouse model of ischemia/reperfusion (IR)-induced liver sterile inflammatory injury, we found that adoptive transfer of MSCs reduced hepatocellular damage, shifted macrophage polarization from M1 to M2 phenotype, and diminished inflammatory mediators. MSC treatment reduced MST1/2 and LATS1 phosphorylation but augmented YAP and β-catenin expression with increased PGE2 production in ischemic livers. However, disruption of myeloid YAP or β-catenin in MSC-transferred mice exacerbated IR-triggered liver inflammation, enhanced NLRP3/caspase-1 activity and reduced M2 macrophage phenotype. Using MSC/macrophage co-culture system, we found that MSCs increased macrophage YAP and β-catenin nuclear translocation. Importantly, YAP and β-catenin co-localize in the nucleus while YAP interacts with β-catenin and regulates its target gene XBP1 leading to reduced NLRP3/caspase-1 activity after co-culture. Moreover, macrophage YAP or β-catenin deficiency augmented XBP1/NLRP3 while XBP1 deletion diminished NLRP3/caspase-1 activity. Increasing NLRP3 expression reduced M2 macrophage Arg1 but augmented M1 macrophage iNOS expression accompanied by increased IL-1β release. Conclusion: MSCs promote macrophage Hippo pathway, which in turn controls NLRP3 activation through a direct interaction between YAP and β-catenin and regulates XBP1-mediated NLRP3 activation leading to reprograming macrophage polarization towards an anti-inflammatory M2 phenotype. Moreover, YAP functions as a transcriptional co-activator of β-catenin in MSC-mediated immune regulation. Our findings provide a novel therapeutic target in MSC-mediated immunotherapy of liver sterile inflammatory injury. This article is protected by copyright. All rights reserved.


YAP ; Innate immunity; Liver inflammation; Macrophage polarization; β-catenin


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