WNT ligands contribute to the immune response during septic shock and amplify endotoxemia-driven inflammation in mice

Gatica-Andrades, Marcela; Vagenas, Dimitrios; Kling, Jessica C.; Nguyen, Tam T.; Benham, Helen; Thomas, Ranjeny; Körner, Heinrich; Venkatesh, Balasubramanian; Cohen, Jérémy; Blumenthal, Antje

doi:10.1182/bloodadvances.2017006163

Cited by 40 publications

(42 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it is important to note that β-catenin activity in regulatory T cells impairs their functions and drives colitis and tumor development ( 44 , 45 ). Moreover, we recently demonstrated that pharmacologic targeting of both β-catenin activity and Wnt production impaired pro-inflammatory cytokine responses in an endotoxemia model in mice ( 46 ), indicating pro-inflammatory functions of Wnt/β-catenin signaling in this context. Future studies will focus on identifying individual Wnt/Wnt receptor combinations that shape NKT cell functions and fate, as well as the specific cellular sources of the Wnt ligands that regulate cytokine production by NKT cells.…”

Section: Discussionmentioning

confidence: 99%

Temporal Regulation of Natural Killer T Cell Interferon Gamma Responses by β-Catenin-Dependent and -Independent Wnt Signaling

et al. 2018

Self Cite

View full text Add to dashboard Cite

Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-γ) and IL-4 are key cytokines rapidly produced by NKT cells upon recognition of glycolipid antigens presented by antigen-presenting cells (APCs). It has previously been reported that the transcriptional coactivator β-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-γ production. β-Catenin is not only a central effector of Wnt signaling but also contributes to other signaling networks. It is currently unknown whether Wnt ligands regulate NKT cell functions. We thus investigated how Wnt ligands and β-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, α-galactosylceramide (α-GalCer) using a mouse model. Pharmacologic targeting of β-catenin activity with ICG001, as well as myeloid-specific genetic ablation of Wntless (Wls), to specifically target Wnt protein release by APCs, enhanced early IFN-γ responses. By contrast, within several hours of α-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired α-GalCer-induced IFN-γ responses, independent of β-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/β-catenin signaling that curbs IFN-γ responses, but that, subsequently, Wnt ligands sustain IFN-γ expression independent of β-catenin activity. Our analyses in ICG001-treated mice confirmed a role for β-catenin activity in driving early IL-4 responses by liver NKT cells. However, neither pharmacologic nor genetic perturbation of Wnt production affected the IL-4 response, suggesting that IL-4 production by NKT cells in response to α-GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and β-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of β-catenin to NKT cell functions.

show abstract

Section: Discussionmentioning

confidence: 99%

Temporal Regulation of Natural Killer T Cell Interferon Gamma Responses by β-Catenin-Dependent and -Independent Wnt Signaling

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…This signaling has been reported elsewhere to exert the anti-inflammatory or pro-inflammatory properties [35][36][37][38][39]. Indeed, in the intestine the activation of Wnt/beta-catenin pathway helps to maintain GVB function [2,34].…”

Section: Discussionmentioning

confidence: 99%

Berberine Exerts a Protective Effect on Gut-Vascular Barrier via the Modulation of the Wnt/Beta-Catenin Signaling Pathway During Sepsis

Yuan

Zuo

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The gut-vascular barrier (GVB) has recently been depicted to dampen the bacterial invasion of the bloodstream. The intestinal mucosa is a tissue rich in small vessels including capillaries. In this study, the protective effect of berberine on GVB in small bowel mucosa was investigated. Methods: The rat cecal ligation and puncture (CLP) sepsis model was employed to evaluate the effect of berberine on serum endotoxin level and intestinal vascular permeability to Evans blue in vivo. The rat intestinal microvascular endothelial cells (RIMECs) treated by lipopolysaccharide (LPS) were used to assess the effect of berberine on endothelial permeability to FITC-labeled dextran, transendothelial electrical resistance (TEER), and tight junction (TJ) and adherens junction (AJ) expression in vitro. Results: After 24-hr CLP operation the serum endotoxin concentration and gut vascular permeability were significantly increased, while berberine markedly reduced endotoxin level and vascular leakage. In vitro, LPS not only dramatically increased endothelial permeability of RIMECs to FITC-dextran, but also decreased TEER and inhibited claudin-12, beta-catenin and VE-cadherin expression. These effects of LPS were antagonized by berberine. In addition, our in vivo and vitro studies also confirmed that the effect of berberine on GVB could be partially abolished by ICG001. Conclusion: Berberine exerted a protective effect on GVB function in sepsis, which was strictly related to the modulation of the Wnt/beta-catenin signaling pathway.

show abstract

“…In addition to their roles in inflammation, recent studies have reported that these Wnt ligands play key roles in tissue damage and repair [ 6 ]. Interestingly, previous studies have reported significant alterations in Wnt5a and Wnt11 expression compared to other Wnt ligands by analysing sera of patients with severe sepsis or sepsis mouse model [ 4 , 8 ]. Wnt5a signalling has been known to activate in sepsis or ARDS and play a pivotal role in lung inflammation and fibrosis [ 5 , 9 ], whereas Wnt11 protein has been reported to suppress induction of inflammatory cytokines by regulating NF-κB activity [ 10 , 11 ].…”

mentioning

confidence: 99%

Wnt5a and Wnt11 as acute respiratory distress syndrome biomarkers for severe acute respiratory syndrome coronavirus 2 patients

et al. 2020

View full text Add to dashboard Cite

The coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread globally, thereby resulting in declaration of pandemic emergency [1]. COVID-19 patients suffer from various infectious symptoms, including pneumonia, acute respiratory distress syndrome (ARDS) and sepsis. Some known-antiviral drugs, including remdesivir, have been proposed as effective agents for the treatment of SARS-CoV-2 infection [2, 3]. Along with the development of potential therapeutics, there is also urgency to mitigate the transmission and economic crisis of SARS-CoV-2 via identification of biomarkers that can rapidly indicate the severity of the disease in infected patients. Wnt ligands are secreted glycoproteins and their downstream signalling plays a pivotal role in embryonic development and tissue homeostasis. With remarkable progress in the immunology field, Wnt signalling has gained much attention as a critical regulator in various inflammatory diseases. A large body of evidence has suggested that Wnt ligands were secreted by immune cells, such as PBMCs, and non-immune cells, including stroma cell, to regulate inflammatory response and immune cell modulation [4–7]. In addition to their roles in inflammation, recent studies have reported that these Wnt ligands play key roles in tissue damage and repair [6]. Interestingly, previous studies have reported significant alterations in Wnt5a and Wnt11 expression compared to other Wnt ligands by analysing sera of patients with severe sepsis or sepsis mouse model [4, 8]. Wnt5a signalling has been known to activate in sepsis or ARDS and play a pivotal role in lung inflammation and fibrosis [5, 9], whereas Wnt11 protein has been reported to suppress induction of inflammatory cytokines by regulating NF-κB activity [10, 11]. Previous reports have demonstrated that Wnt5a and Wnt11 have opposite functions to one another in response to inflammation [12, 13]; hence it is thought that Wnt5a has pro-inflammatory effect and Wnt11 may be anti-inflammatory effect. Therefore, we focused on Wnt5a and Wnt11 to explore their potential relevance to COVID-19-related diseases. In this study, we report Wnt5a and Wnt11 as reliable biomarkers for monitoring of pathological progression in SARS-CoV-2 patients.

show abstract

WNT ligands contribute to the immune response during septic shock and amplify endotoxemia-driven inflammation in mice

Cited by 40 publications

References 56 publications

Temporal Regulation of Natural Killer T Cell Interferon Gamma Responses by β-Catenin-Dependent and -Independent Wnt Signaling

Temporal Regulation of Natural Killer T Cell Interferon Gamma Responses by β-Catenin-Dependent and -Independent Wnt Signaling

Berberine Exerts a Protective Effect on Gut-Vascular Barrier via the Modulation of the Wnt/Beta-Catenin Signaling Pathway During Sepsis

Wnt5a and Wnt11 as acute respiratory distress syndrome biomarkers for severe acute respiratory syndrome coronavirus 2 patients

Contact Info

Product

Resources

About