Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1–mediated neutrophilic acute lung inflammation

Guo, Yujie; Mishra, Amarjit; Howland, Emily; Zhao, Chunling; Shukla, Dhananjay; Weng, Tingting; Liu, Lin

doi:10.1182/blood-2015-02-622233

Cited by 78 publications

(56 citation statements)

References 62 publications

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“…b-Catenin stabilization was shown to occur via deubiquitination by a complex of Rnf220 and the ubiquitinspecific protease 7 (71). Promotion of Wnt/b-catenin signaling by canonical ligand, Wnt3a, and inhibition of Wnt antagonist, Dkk1, has been shown to decrease LPSinduced neutrophil influx and cytokine production (72). In addition, ghrelin has been shown to rescue LPS-induced inhibition of b-catenin, LPS-induced apoptosis in alveolar Mfs, and outcomes in a model of the acute respiratory distress syndrome in rats (73).…”

Section: Discussionmentioning

confidence: 99%

Genetic determinants of susceptibility to silver nanoparticle‐induced acute lung inflammation in mice

et al. 2017

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Silver nanoparticles (AgNPs) are employed in a variety of consumer products; however, rodent studies indicate that AgNPs can cause lung inflammation and toxicity in a strain- and particle type-dependent manner, but mechanisms of susceptibility remain unclear. The aim of this study was to assess the variation in AgNP-induced lung inflammation and toxicity across multiple inbred mouse strains and to use genome-wide association (GWA) mapping to identify potential candidate susceptibility genes. Mice received doses of 0.25 mg/kg of either 20-nm citrate-coated AgNPs or citrate buffer using oropharyngeal aspiration. Neutrophils in bronchoalveolar lavage fluid (BALF) served as markers of inflammation. We found significant strain- and treatment-dependent variation in neutrophils in BALF. GWA mapping identified 10 significant single-nucleotide polymorphisms (false discovery rate, 15%) in 4 quantitative trait loci on mouse chromosomes 1, 4, 15, and 18, and (neural precursor cell expressed developmentally downregulated gene 4-like; chromosome 18), (anocatmin 6; chromosome 15), and (Ring finger protein 220; chromosome 4) were considered candidate genes. Quantitative RT-PCR revealed significant inverse associations between mRNA levels of these genes and neutrophil influx. ,, and are candidate susceptibility genes for AgNP-induced lung inflammation that warrant additional exploration in future studies.-Scoville, D. K., Botta, D., Galdanes, K., Schmuck, S. C., White, C. C., Stapleton, P. L., Bammler, T. K., MacDonald, J. W., Altemeier, W. A., Hernandez, M., Kleeberger, S. R., Chen, L.-C., Gordon, T., Kavanagh, T. J. Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice.

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Section: Discussionmentioning

confidence: 99%

Genetic determinants of susceptibility to silver nanoparticle‐induced acute lung inflammation in mice

et al. 2017

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“…Very recent reports including ours in the field showed pro-inflammatory roles of DKK-1 in various diseases such as asthma, parasitic or viral infection and cancer. [16][17][18]31 The role of DKK-1 in Treg cells is to control unwanted inflammation that is very different from its previously known role as a pro-inflammatory ligand. A possible explanation of this context-dependent role of DKK-1 is that the role of DKK-1 could be multifunctional in a given inflammatory milieu.…”

Section: Discussionmentioning

confidence: 99%

Membrane‐bound Dickkopf‐1 in Foxp3⁺ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis

et al. 2017

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SummaryInduction of tolerance is a key mechanism to maintain or to restore immunological homeostasis. Here we show that Foxp3+ regulatory T (Treg) cells use Dickkopf‐1 (DKK‐1) to regulate T‐cell‐mediated tolerance in the T‐cell‐mediated autoimmune colitis model. Treg cells from DKK‐1 hypomorphic doubleridge mice failed to control CD4+ T‐cell proliferation, resulting in CD4 T‐cell‐mediated autoimmune colitis. Thymus‐derived Treg cells showed a robust expression of DKK‐1 but not in naive or effector CD4 T cells. DKK‐1 expression in Foxp3+ Treg cells was further increased upon T‐cell receptor stimulation in vitro and in vivo. Interestingly, Foxp3+ Treg cells expressed DKK‐1 in the cell membrane and the functional inhibition of DKK‐1 using DKK‐1 monoclonal antibody abrogated the suppressor function of Foxp3+ Treg cells. DKK‐1 expression was dependent on de novo protein synthesis and regulated by the mitogen‐activated protein kinase pathway but not by the canonical Wnt pathway. Taken together, our results highlight membrane‐bound DKK‐1 as a novel Treg‐derived mediator to maintain immunological tolerance in T‐cell‐mediated autoimmune colitis.

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“…On day 14 mice were sacrificed, and lung tissues were collected. Fibroblasts and alveolar epithelial type II cells (AEC II) were isolated from the lungs of saline or bleomycin-treated mice according to the previously described protocols [16, 17]. Alveolar epithelial type I cells (AEC I) were obtained by culturing AEC II in Dulbecco’s Modified Eagle Medium (DMEM) for 5 days [18].…”

Section: Methodsmentioning

confidence: 99%

miR-27b inhibits fibroblast activation via targeting TGFβ signaling pathway

et al. 2017

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BackgroundMicroRNAs are a group of small RNAs that regulate gene expression at the posttranscriptional level. They regulate almost every aspect of cellular processes. In this study, we investigated whether miR-27b regulates pulmonary fibroblast activation.ResultsWe found that miR-27b was down-regulated in fibrotic lungs and fibroblasts from an experimental mouse model of pulmonary fibrosis. The overexpression of miR-27b with a lentiviral vector inhibited TGFβ1-stimulated mRNA expression of collagens (COL1A1, COL3A1, and COL4A1) and alpha-smooth muscle actin, and protein expression of Col3A1 and alpha-smooth muscle actin in LL29 human pulmonary fibroblasts. miR-27b also reduced contractile activity of LL29. TGFβ receptor 1 and SMAD2 were identified as the targets of miR-27b by 3’-untranslated region luciferase reporter and western blotting assays.ConclusionsOur results suggest that miR-27b is an anti-fibrotic microRNA that inhibits fibroblast activation by targeting TGFβ receptor 1 and SMAD2. This discovery may provide new targets for therapeutic interventions of idiopathic pulmonary fibrosis.

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Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1–mediated neutrophilic acute lung inflammation

Abstract: Key Points Platelet-derived Dkk1 is the major Wnt antagonist that suppresses Wnt/β-catenin signaling during acute lung inflammation. Intratracheal administration of Wnt3a or neutralization of Dkk1 inhibited neutrophil influx into the lungs.

Cited by 78 publications

References 62 publications

Genetic determinants of susceptibility to silver nanoparticle‐induced acute lung inflammation in mice

Genetic determinants of susceptibility to silver nanoparticle‐induced acute lung inflammation in mice

Membrane‐bound Dickkopf‐1 in Foxp3⁺ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis

miR-27b inhibits fibroblast activation via targeting TGFβ signaling pathway

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Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1–mediated neutrophilic acute lung inflammation

Abstract: Key Points Platelet-derived Dkk1 is the major Wnt antagonist that suppresses Wnt/β-catenin signaling during acute lung inflammation. Intratracheal administration of Wnt3a or neutralization of Dkk1 inhibited neutrophil influx into the lungs.

Cited by 78 publications

References 62 publications

Genetic determinants of susceptibility to silver nanoparticle‐induced acute lung inflammation in mice

Genetic determinants of susceptibility to silver nanoparticle‐induced acute lung inflammation in mice

Membrane‐bound Dickkopf‐1 in Foxp3+ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis

miR-27b inhibits fibroblast activation via targeting TGFβ signaling pathway

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Membrane‐bound Dickkopf‐1 in Foxp3⁺ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis