Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

Ramjee, Vimal; Li, Deqiang; Manderfield, Lauren J.; Liu, Feiyan; Engleka, Kurt A.; Aghajanian, Haig; Rodell, Christopher B.; Lu, Wenyue; Ho, Vivienne C.; Wang, Tao; Li, Li; Singh, Anamika; Cibi, Dasan Mary; Burdick, Jason A.; Singh, Manvendra K.; Jain, Rajan; Epstein, Jonathan A.

doi:10.1172/jci88759

Cited by 134 publications

(123 citation statements)

References 84 publications

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“…Nevertheless, it was unclear what function the upregulation of Hippo pathway components and YAP played in activated CD8 cells. One study reported that interferon regulator factor 3 (IRF3) promotes nuclear translocation and activity of YAP in response to antiviral signaling in gastric cell lines, and another that deletion of YAP and TAZ in cardiomyocytes caused severe IFNγ-driven pericardial inflammation and fibrosis (30,31). However, such evidence falls short of associating the terminal Hippo pathway effectors YAP and TAZ to a functional role in CD8 cells, and the therapeutic potential for targeting these factors in the cancer setting remains incompletely explored.…”

Section: Discussionmentioning

confidence: 99%

YAP Attenuates CD8 T Cell-Mediated Anti-tumor Response

et al. 2020

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YAP is a transcriptional coactivator of the Hippo signaling pathway that has largely been studied for its role in the regulation of organ size during development. Several studies have shown that YAP is upregulated in cancer cells, and more recently in the T regulatory (Treg) subset of CD4+ cells. These observations suggest that the transcriptional co-activator may promote tumor persistence and progression. Here, we report that YAP also plays an immunoinhibitory role in CD8 T cells, especially in activated cytotoxic cells usually found in the tumor microenvironment. Our findings add further rationale for the development and use of pharmacologic inhibitors of YAP to treat cancer.

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Section: Discussionmentioning

confidence: 99%

YAP Attenuates CD8 T Cell-Mediated Anti-tumor Response

et al. 2020

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“…Moreover, recent evidence has indicated that Hippo signaling regulates innate immunity through a YAP‐mediated transcriptional mechanism . Activation of YAP inhibited immune response, whereas YAP deficiency resulted in aggravated tissue inflammatory injury …”

mentioning

confidence: 99%

Hippo Signaling Controls NLR Family Pyrin Domain Containing 3 Activation and Governs Immunoregulation of Mesenchymal Stem Cells in Mouse Liver Injury

Jin²,

Song³

et al. 2019

Hepatology

106

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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 NLR family pyrin domain containing 3 (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 mammalian Ste20-like kinase 1/2 and large tumor suppressor 1 phosphorylation but augmented YAP and β-catenin expression with increased prostaglandin E2 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 coculture system, we found that MSCs increased macrophage YAP and β-catenin nuclear translocation. Importantly, YAP and β-catenin colocalize in the nucleus while YAP interacts with β-catenin and regulates its target gene X-box binding protein 1 (XBP1), leading to reduced NLRP3/caspase-1 activity after coculture. Moreover, macrophage YAP or β-catenin deficiency augmented XBP1/NLRP3 while XBP1 deletion diminished NLRP3/caspase-1 activity. Increasing NLRP3 expression reduced M2 macrophage arginase1 but augmented M1 macrophage inducible nitric oxide synthase expression accompanied by increased interleukin-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 toward an anti-inflammatory M2 phenotype. Moreover, YAP functions as a transcriptional coactivator of β-catenin in MSC-mediated immune regulation. Our findings suggest a therapeutic target in MSC-mediated immunotherapy of liver sterile inflammatory injury.

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“…Mechanistically, YAP/TAZ induce the epicardial expression of interferon γ (IFNγ), which is an inducer of Treg cells. In their study, Ramjee et al () showed that the local delivery of IFNγ after myocardial infarction attenuated fibrosis development in the hearts of epicardial‐specific Yap/Taz knockout mice, which indicates that the Hippo pathway in the epicardium is essential for heart repair (Figure ).…”

Section: The Role Of the Hippo Pathway In Heart Regenerationmentioning

confidence: 99%

“…Wang, Karra, Dickson, & Poss, 2013). Ramjee et al showed that YAP/TAZ play an essential role in epicardial cells in recruiting T-regulatory (Treg) cells to the injury site (Ramjee et al 2017). Treg cells suppress inflammation and promote cardiac repair (Hofmann et al, 2012;Nahrendorf & Swirski, 2014;Weirather et al, 2014).…”

Section: Hippo/yap Regulate Inflammation In Response To Injurymentioning

confidence: 99%

The regulation and function of the Hippo pathway in heart regeneration

Liu¹,

Martin

2018

WIREs Developmental Biology

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Heart failure caused by cardiomyocyte loss and fibrosis is a leading cause of death worldwide. Although current treatments for heart failure such as heart transplantation and left ventricular assist device implantation have obvious value, new approaches are needed. Endogenous adult cardiomyocyte renewal is measurable but inefficient and inadequate in response to extensive acute heart damage. Stimulating self-renewal of endogenous cardiomyocytes holds great promise for heart repair. Uncovering the genetic mechanisms underlying cardiomyocyte renewal is a critical step in developing new approaches to repairing the heart. Recent studies have revealed that the inhibition of the Hippo pathway is sufficient to promote the proliferation of endogenous cardiomyocytes, indicating that the manipulation of the Hippo pathway in the heart may be a promising treatment for heart failure in the future. We summarize recent findings that have shed light on the function of the Hippo pathway in heart regeneration. We also discuss the mechanisms by which Hippo pathway inhibition promotes heart regeneration and how the Hippo pathway responds to different types of injury or stress during the regenerative process. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration.

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Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

Cited by 134 publications

References 84 publications

YAP Attenuates CD8 T Cell-Mediated Anti-tumor Response

YAP Attenuates CD8 T Cell-Mediated Anti-tumor Response

Hippo Signaling Controls NLR Family Pyrin Domain Containing 3 Activation and Governs Immunoregulation of Mesenchymal Stem Cells in Mouse Liver Injury

The regulation and function of the Hippo pathway in heart regeneration

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