Canonical and Non-Canonical Wnt Signaling in Immune Cells

Chae, Wook Jin; Bothwell, Alfred L.M.

doi:10.1016/j.it.2018.08.006

Cited by 129 publications

(112 citation statements)

References 114 publications

(153 reference statements)

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“…The results also discard the possibility that the presence of IL-36g changes the signaling pathway mediated by WNT5A leading to bacterial killing. In addition, JNK and NF-kB are downstream pathways of noncanonical WNT signaling pathway (19,29,30). Ours results showed that both rhIL-36g and rhWNT5A induced increased p-JNK and p-p65 ( Fig.…”

Section: Il-36g Mediated the Bactericidal Activity Partly Through Thementioning

confidence: 60%

“…In this study, we confirmed that IL-36g suppresses M. tuberculosis growth in macrophages by triggering WNT5A-induced noncanonical WNT signaling-mediated autophagy. Our study revealed that IL-36g or WNT5A can activated the noncanonical WNT pathway by inducing JNK and p65 phosphorylation (19,29,30), although the specific downstream mechanisms are worthy to be studied. Furthermore, we have filled in the pathway of WNT5A-induced autophagy, verifying it was mediated by COX-2, a key rate-limiting enzyme in the arachidonic acid pathway, and subsequent inactivation of AKT/mTOR signaling.…”

Section: Discussionmentioning

confidence: 83%

“…WNT5A belongs to the WNT family of glycoprotein signal transducers. Two main branches of classical WNT signaling cascades have been demonstrated: b-catenin-dependent (canonical) and b-catenin-independent (noncanonical) WNT signaling, the use of which depends on the context (19,20). Many studies indicated that WNT5A exerts proinflammatory functions on various types of immune and nonimmune cells, thus playing key roles in tissue homeostasis and modulation of immune responses in pathology (21,22).…”

Section: Il-36g Promotes Killing Of Mycobacterium Tuberculosis By Macmentioning

confidence: 99%

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IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

Gao

Wen

et al. 2019

The Journal of Immunology

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Mycobacterium tuberculosis, which primarily infects mononuclear phagocytes, remains the leading bacterial cause of enormous morbidity and mortality because of bacterial infections in humans throughout the world. The IL-1 family of cytokines is critical for host resistance to M. tuberculosis. As a newly discovered subgroup of the IL-1 family, although IL-36 cytokines have been proven to play roles in protection against M. tuberculosis infection, the antibacterial mechanisms are poorly understood. In this study, we demonstrated that IL-36γ conferred to human monocyte-derived macrophages bacterial resistance through activation of autophagy as well as induction of WNT5A, a reported downstream effector of IL-1 involved in several inflammatory diseases. Further studies showed that WNT5A could enhance autophagy of monocyte-derived macrophages by inducing cyclooxygenase-2 (COX-2) expression and in turn decrease phosphorylation of AKT/mTOR via noncanonical WNT signaling. Consistently, the underlying molecular mechanisms of IL-36γ function are also mediated by the COX-2/AKT/mTOR signaling axis. Altogether, our findings reveal a novel activity for IL-36γ as an inducer of autophagy, which represents a critical inflammatory cytokine that control the outcome of M. tuberculosis infection in human macrophages.

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Section: Il-36g Mediated the Bactericidal Activity Partly Through Thementioning

confidence: 60%

Section: Discussionmentioning

confidence: 83%

Section: Il-36g Promotes Killing Of Mycobacterium Tuberculosis By Macmentioning

confidence: 99%

See 1 more Smart Citation

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

Gao

Wen

et al. 2019

The Journal of Immunology

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“…Genes regulated by Yap include several key effectors of T cell activation, including those controlling JAK-STAT signaling that modulate the polarization of naïve CD4s into T helper subsets (Seif et al, 2017). Notably, Yapregulated genes are also enriched for those regulated by the TGFb and Wnt pathways, which have important pleotropic roles in T cell biology (Batlle and Massague, 2019;Chae and Bothwell, 2018). Given the known convergence of Yap with these immunomodulatory pathways (Varelas and Wrana, 2012) it is likely Yap directs their transcriptional targets and signal strength.…”

Section: Discussionmentioning

confidence: 99%

Yap suppresses T cell function and infiltration in the tumor microenvironment

Stampouloglou

Federico

Slaby

et al. 2019

Preprint

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A major challenge for cancer immunotherapy is sustaining T cell activation and recruitment in immunosuppressive solid tumors. Here we report that Yap levels are sharply induced upon CD4 + and CD8 + T cell activation and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap results in enhanced T cell activation, differentiation and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicatesYap as a mediator of global T cell responses in the tumor microenvironment and as a key negative regulator of T cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T cell biology, and suggest that inhibiting Yap activity improves T cell responses in cancer.

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“…Specifically, ZEB2 is involved in T cell differentiation (Goossens et al, 2019) and neurological development (Epifanova et al, 2018). LEF1 is important during osteogenesis (Li et al, 2018), immune cell regulation (Chae and Bothwell, 2018), and hair follicle development (Abaci et al, 2018). ETS1 is an important regulator of lymphatic cell differentiation and physiology (Garrett-Sinha et al, 2016).…”

Section: Robustness Analysismentioning

confidence: 99%

A Computational Model of the Endothelial to Mesenchymal Transition

2020

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Endothelial cells (ECs) form the lining of lymph and blood vessels. Changes in tissue requirements or wounds may cause ECs to behave as tip or stalk cells. Alternatively, they may differentiate into mesenchymal cells (MCs). These processes are known as EC activation and endothelial-to-mesenchymal transition (EndMT), respectively. EndMT, Tip, and Stalk EC behaviors all require SNAI1, SNAI2, and Matrix metallopeptidase (MMP) function. However, only EndMT inhibits the expression of VE-cadherin, PECAM1, and VEGFR2, and also leads to EC detachment. Physiologically, EndMT is involved in heart valve development, while a defective EndMT regulation is involved in the physiopathology of cardiovascular malformations, congenital heart disease, systemic and organ fibrosis, pulmonary arterial hypertension, and atherosclerosis. Therefore, the control of EndMT has many promising potential applications in regenerative medicine. Despite the fact that many molecular components involved in EC activation and EndMT have been characterized, the system-level molecular mechanisms involved in this process have not been elucidated. Toward this end, hereby we present Boolean network model of the molecular involved in the regulation of EC activation and EndMT. The simulated dynamic behavior of our model reaches fixed and cyclic patterns of activation that correspond to the expected EC and MC cell types and behaviors, recovering most of the specific effects of simple gain and loss-of-function mutations as well as the conditions associated with the progression of several diseases. Therefore, our model constitutes a theoretical framework that can be used to generate hypotheses and guide experimental inquiry to comprehend the regulatory mechanisms behind EndMT. Our main findings include that both the extracellular microevironment and the pattern of molecular activity within the cell regulate EndMT. EndMT requires a lack of VEGFA and sufficient oxygen in the extracellular microenvironment as well as no FLI1 and GATA2 activity within the cell. Additionally Tip cells cannot undergo EndMT directly. Furthermore, the specific conditions that are sufficient to trigger EndMT depend on the specific pattern of molecular activation within the cell.

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Canonical and Non-Canonical Wnt Signaling in Immune Cells

Cited by 129 publications

References 114 publications

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

Yap suppresses T cell function and infiltration in the tumor microenvironment

A Computational Model of the Endothelial to Mesenchymal Transition

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