Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis

Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low, and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.

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A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models

Human Molecular Genetics ◽

10.1093/hmg/ddz293 ◽

2019 ◽

Vol 29 (2) ◽

pp. 274-285 ◽

Cited By ~ 1

Author(s):

Roberto Costa ◽

Stefania Bellesso ◽

Susanna Lualdi ◽

Rosa Manzoli ◽

Valeria Pistorio ◽

...

Keyword(s):

Wnt Signaling ◽

Gaucher Disease ◽

Wnt Pathway ◽

Experimental Models ◽

Type I ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Bone Differentiation

Abstract Bone differentiation defects have been recently tied to Wnt signaling alterations occurring in vitro and in vivo Gaucher disease (GD) models. In this work, we provide evidence that the Wnt signaling multi-domain intracellular transducers Dishevelled 1 and 2 (DVL1 and DVL2) may be potential upstream targets of impaired beta glucosidase (GBA1) activity by showing their misexpression in different type 1 GD in vitro models. We also show that in Gba mutant fish a miR-221 upregulation is associated with reduced dvl2 expression levels and that in type I Gaucher patients single-nucleotide variants in the DVL2 3′ untranslated region are related to variable canonical Wnt pathway activity. Thus, we strengthen the recently outlined relation between bone differentiation defects and Wnt/β-catenin dysregulation in type I GD and further propose novel mechanistic insights of the Wnt pathway impairment caused by glucocerebrosidase loss of function.

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Linking Frizzled and Wnt signaling in Drosophila development

Development ◽

10.1242/dev.124.22.4515 ◽

1997 ◽

Vol 124 (22) ◽

pp. 4515-4521 ◽

Cited By ~ 8

Author(s):

A. Tomlinson ◽

W.R. Strapps ◽

J. Heemskerk

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Pathway ◽

Wnt Signaling Pathway ◽

Loss Of Function ◽

Planar Polarity ◽

Culture Cells ◽

Second Messenger Systems ◽

Retinal Epithelium ◽

Embryonic Ectoderm

Drosophila Frizzled-2 (Dfz2) has been identified as a putative fly Wingless (Wg) receptor. Although Dfz2 shows significant homology with Fz, a protein that operates in the mechanisms that establish planar polarity in Drosophila epithelia, any clear evidence for an involvement by Fz in a Wnt signaling pathway has hitherto been absent. Here we describe the planar polarity phenotypes of loss-of-function and overexpression of Fz in the developing Drosophila eye and find it almost identical to the loss-of-function or overexpression of Dishevelled (Dsh - a protein operating in Wnt second messenger systems). In addition, we show that overexpression of Shaggy (Sgg - another component of the Wnt pathway) in the eye also causes a phenotype similar to Fz and Dsh. To test further the link between planar polarity and Wnt signaling we misexpressed Wg in the developing eye and found it had a potent polarizing effect in the retinal epithelium. Since the overexpression of Fz in the developing eye gave a phenotype consistent with activating the Wnt pathway, we tested overexpression of Fz in the developing embryonic ectoderm and found that it phenocopied overexpression of Wg. To check that Fz was indeed able to activate a Wnt pathway we overexpressed it in Drosophila tissue culture cells and observed the characteristic phosphorylation of Dsh that occurs in response to Wnt signaling. Taken together our results significantly strengthen the case for Fz acting in a Wnt signaling pathway in Drosophila.

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Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

Cancers ◽

10.3390/cancers13143446 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3446

Author(s):

Stefan Koch

Keyword(s):

Transcription Factors ◽

Wnt Signaling ◽

Wnt Pathway ◽

Treatment Options ◽

Wnt Signaling Pathway ◽

Tissue Homeostasis ◽

Fine Tuning ◽

Dependent Manner ◽

Forkhead Box ◽

Signaling Activity

Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers.

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Abstract TMP68: Vulnerability to Health Disparities and Secondary Stroke Prevention: The REGARDS Study

Stroke ◽

10.1161/str.47.suppl_1.tmp68 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

James. D Rhodes ◽

Asikhame Oikeh ◽

Chris Gamboa ◽

Abimbola Fadairo ◽

Suzanne Judd ◽

...

Keyword(s):

Health Disparities ◽

Stroke Prevention ◽

Healthcare Providers ◽

Lipid Lowering ◽

Inverse Association ◽

Secondary Stroke Prevention ◽

Stroke Event ◽

Point Increase ◽

National Cohort ◽

Regards Study

There are few studies on the effect of multiple vulnerabilities to health disparities identified in the AHRQ 2012 report on secondary stroke prevention. We examined the effects of 5 vulnerability domains (race, age, region, health insurance and income) on the prescription of secondary stroke prevention medications at discharge following hospitalization for an acute ischemic stroke (AIS) in a large, national cohort of patients admitted to unselected hospitals. Methods: We conducted a retrospective review of admissions for AIS between 2003-2012 within the REGARDS cohort. Discharge medications, insurance status, and age at time of stroke event were obtained from hospital records. Race, region and income < $20,000 were obtained from REGARDS baseline data. We constructed a vulnerability score (v score) range from 0-5, with 0 indicating no vulnerability. We examined the prevalence of each discharge medication by each vulnerability domain, score category, and by overall score using Poisson regression with a robust variance estimator. Results: 664 participants met the inclusion criteria. 132 (20%) of the study participants had ≥ 3 vulnerabilities (v score of 3-5). Participants with ≥ 3 vulnerabilities were more likely to be black (80.3%), > 75 years old (63.6%), and to report income < $20,000 (67.4%). The prevalence of receiving antithrombotic prescriptions at discharge was significantly lower in participants with ≥ 3 vulnerability domains (PR: 0.90 [95% CI: 0.82, 0.99]). The prevalence of receiving antithrombotic prescriptions was also inversely associated with a per point increase of the v score (PR: 0.96 [95% CI: 0.93, 0.99]), as were lipid- lowering prescriptions at discharge (PR: 0.95 [CI: 0.90, 0.99]). There was a non-statistically significant inverse association between ACEi/ARB prescriptions at discharge and having multiple vulnerabilities, including for 2 vulnerabilities (PR: 0.93 [CI: 0.80, 1.09]) and for ≥ 3 vulnerabilities (PR: 0.84 [CI: 0.69, 1.01]). Conclusion: The presence of multiple vulnerabilities was associated with lower adherence by healthcare providers to secondary stroke prevention recommendations for discharge prescriptions.

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Chronic inflammation of the prostate type IV with respect to risk of prostate cancer

Archivio Italiano di Urologia e Andrologia ◽

10.4081/aiua.2014.3.208 ◽

2014 ◽

Vol 86 (3) ◽

pp. 208 ◽

Cited By ~ 11

Author(s):

Antonio B. Porcaro ◽

Emanuele Rubilotta ◽

Aldo Petrozziello ◽

Claudio Ghimenton ◽

Filippo Migliorini ◽

...

Keyword(s):

Prostate Cancer ◽

Chronic Inflammation ◽

Inverse Association ◽

Single Centre ◽

Type Iv ◽

Assessment Design ◽

Biopsy Specimens ◽

Positive Biopsy ◽

Biopsy Core ◽

Glandular Atrophy

Background: Chronic inflammatory infiltrate (CII) might be involved in prostate cancer (PCA) and benign hyperplasia (BPH); however, its significance is controversial. Chronic inflammatory prostatitis type IV is the most common non cancer diagnosis in men undergoing biopsy because of suspected PCA. Objective: To evaluate potential associations of coexistent CII and PCA in biopsy specimens after prostate assessment. Design, setting, and participants: Between January 2007 and December 2008, 415 consecutive patients who underwent prostate biopsy were retrospectively evaluated. The investigated variables included Age (years) and PSA (ug/l); moreover, CII+, glandular atrophy (GA+), glandular hyperplasia (GH+), prostate Intraepithelial neoplasm (PIN+), atypical small acinar cell proliferation (ASAP+) and PCA positive cores (P+) were evaluated as categorical and continuous (proportion of positive cores). Outcome measurements and statistical analysis: Associations of CII+ and PCA risk were assessed by statistical methods. Results and limitations: In the patient population, a biopsy core positive for PCA was detected in 34.2% of cases and the rate of high grade PCA (HGPCA: bGS ! 8) resulted 4.82%. CII+ significantly and inversely associated with a positive biopsy core P+ (P < 0.0001; OR = 0.26) and HGPCA (P = 0.0005; OR = 0.05). Moreover, the associations indicated that patients with coexistent CII+ on needle biopsy were 74% less likely to have coexistent PCA than men without CII+ as well as 95% less likely to have HGPCA in the biopsy core than men without coexistent CII+. There were limits in our study which was single centre and included only one dedicated pathologist. Conclusions: There was an inverse association of chronic inflammation of the prostate type IV and risk of PCA; moreover, HGPCA was less likely to be detected in cancers associated with coexistent CII. In prostate microenvironment, prostate chronic inflammation may be protective; however, its role in PCA carcinogenesis remains controversial and needs further research.

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Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.679568 ◽

2021 ◽

Vol 15 ◽

Author(s):

Bin Li ◽

Guihu Zhao ◽

Qiao Zhou ◽

Yali Xie ◽

Zheng Wang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Association Studies ◽

Age At Onset ◽

Genetic Data ◽

Genome Wide Association Studies ◽

Onset Age ◽

Loss Of Function

Parkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.

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Creating and validating a DNA methylation-based proxy for Interleukin-6

10.1101/2020.07.20.20156935 ◽

2020 ◽

Cited By ~ 2

Author(s):

Anna J Stevenson ◽

Danni A Gadd ◽

Robert Francis Hillary ◽

Daniel L. McCartney ◽

Archie Campbell ◽

...

Keyword(s):

Dna Methylation ◽

Cognitive Functioning ◽

Cognitive Ability ◽

Chronic Inflammation ◽

Interleukin 6 ◽

Epigenetic Mechanism ◽

Inverse Association ◽

Age Related ◽

Independent Test ◽

Methylation Score

Chronic inflammation is a pervasive feature of ageing and may be linked to age-related cognitive decline. However, population studies evaluating its relationship with cognitive functioning have produced heterogeneous results. A potential reason for this is the variability of inflammatory mediators which could lead to misclassifications of individuals' persisting levels of inflammation. The epigenetic mechanism DNA methylation has shown utility in indexing environmental exposures and could potentially be leveraged to provide proxy signatures of chronic inflammation. We conducted an elastic net regression of interleukin-6 (IL-6) in a cohort of 895 older adults (mean age: 69 years) to develop a DNA methylation-based predictor. The predictor was tested in an independent cohort (n=7,028 [417 with measured IL-6], mean age: 51 years).We examined the association between the DNA methylation IL-6 score and serum IL-6, its association with age and established correlates of circulating IL-6, and with cognitive ability. A weighted score from 12 DNA methylation sites optimally predicted IL-6 (independent test set R2=5.1%). In the independent test cohort, both measured IL-6, and the DNA methylation proxy, increased as a function of age (serum IL-6: n=417, β=0.02, SE=0.004 p=1.3x10-7; DNAm IL-6 score: n=7,028, β=0.02, SE=0.0009, p<2x10-16). Serum IL-6 was not found to associate with cognitive ability (n=417, β=-0.06, SE=0.05, p=0.19); however, an inverse association was identified between the DNA methylation score and cognitive functioning (n=7,028, β=-0.14, SE=0.02, pFDR=1.5x10-14). These results suggest DNA methylation-based predictors can be used as proxies for inflammatory markers, potentially allowing for reliable insights into the relationship between chronic inflammation and pertinent health outcomes.

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Extracellular spreading of Wingless is required for Drosophila oogenesis

PLoS Genetics ◽

10.1371/journal.pgen.1009469 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1009469

Author(s):

Xiaoxi Wang ◽

Kimberly S. LaFever ◽

Indrayani Waghmare ◽

Andrea Page-McCaw

Keyword(s):

Stem Cells ◽

Wnt Signaling ◽

Long Range ◽

Wing Disc ◽

Secreted Protein ◽

Loss Of Function ◽

Drosophila Oogenesis ◽

Central Source ◽

Follicle Stem Cells

Recent studies have investigated whether the Wnt family of extracellular ligands can signal at long range, spreading from their source and acting as morphogens, or whether they signal only in a juxtacrine manner to neighboring cells. The original evidence for long-range Wnt signaling arose from studies of Wg, a Drosophila Wnt protein, which patterns the wing disc over several cell diameters from a central source of Wg ligand. However, the requirement of long-range Wg for patterning was called into question when it was reported that replacing the secreted protein Wg with a membrane-tethered version, NRT-Wg, results in flies with normally patterned wings. We and others previously reported that Wg spreads in the ovary about 50 μm or 5 cell diameters, from the cap cells to the follicle stem cells (FSCs) and that Wg stimulates FSC proliferation. We used the NRT-wg flies to analyze the consequence of tethering Wg to the cap cells. NRT-wg homozygous flies are sickly, but we found that hemizygous NRT-wg/null flies, carrying only one copy of tethered Wingless, were significantly healthier. Despite their overall improved health, these hemizygous flies displayed dramatic reductions in fertility and in FSC proliferation. Further, FSC proliferation was nearly undetectable when the wg locus was converted to NRT-wg only in adults, and the resulting germarium phenotype was consistent with a previously reported wg loss-of-function phenotype. We conclude that Wg protein spreads from its source cells in the germarium to promote FSC proliferation.

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Creating and Validating a DNA Methylation-Based Proxy for Interleukin-6

The Journals of Gerontology Series A ◽

10.1093/gerona/glab046 ◽

2021 ◽

Author(s):

Anna J Stevenson ◽

Danni A Gadd ◽

Robert F Hillary ◽

Daniel L McCartney ◽

Archie Campbell ◽

...

Keyword(s):

Dna Methylation ◽

Cognitive Functioning ◽

Chronic Inflammation ◽

Interleukin 6 ◽

Inverse Association ◽

Generation Scotland ◽

Independent Test ◽

Lothian Birth Cohort ◽

Weighted Score ◽

The Relationship

Abstract Background Studies evaluating the relationship between chronic inflammation and cognitive functioning have produced heterogeneous results. A potential reason for this is the variability of inflammatory mediators which could lead to misclassifications of individuals’ persisting levels of inflammation. DNA methylation (DNAm) has shown utility in indexing environmental exposures and could be leveraged to provide proxy signatures of chronic inflammation. Method We conducted an elastic net regression of interleukin-6 (IL-6) in a cohort of 875 older adults (Lothian Birth Cohort 1936; mean age: 70 years) to develop a DNAm-based predictor. The predictor was tested in an independent cohort (Generation Scotland; N = 7028 [417 with measured IL-6], mean age: 51 years). Results A weighted score from 35 CpG sites optimally predicted IL-6 in the independent test set (Generation Scotland; R2 = 4.4%, p = 2.1 × 10−5). In the independent test cohort, both measured IL-6 and the DNAm proxy increased with age (serum IL-6: n = 417, β = 0.02, SE = 0.004, p = 1.3 × 10−7; DNAm IL-6 score: N = 7028, β = 0.02, SE = 0.0009, p < 2 × 10−16). Serum IL-6 did not associate with cognitive ability (n = 417, β = −0.06, SE = 0.05, p = .19); however, an inverse association was identified between the DNAm score and cognitive functioning (N = 7028, β = −0.16, SE = 0.02, pFDR < 2 × 10−16). Conclusions These results suggest methylation-based predictors can be used as proxies for inflammatory markers, potentially allowing for further insight into the relationship between inflammation and pertinent health outcomes.

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A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans

Development ◽

10.1242/dev.126.1.37 ◽

1999 ◽

Vol 126 (1) ◽

pp. 37-49 ◽

Cited By ~ 9

Author(s):

J.N. Maloof ◽

J. Whangbo ◽

J.M. Harris ◽

G.D. Jongeward ◽

C. Kenyon

Keyword(s):

Gene Expression ◽

Wnt Signaling ◽

Wnt Pathway ◽

Hox Genes ◽

Wnt Signaling Pathway ◽

Beta Catenin ◽

Hox Gene ◽

C Elegans ◽

Neuroblast Migration ◽

Pathway Gene

The specification of body pattern along the anteroposterior (A/P) body axis is achieved largely by the actions of conserved clusters of Hox genes. Limiting expression of these genes to localized regional domains and controlling the precise patterns of expression within those domains is critically important for normal patterning. Here we report that egl-20, a C. elegans gene required to activate expression of the Hox gene mab-5 in the migratory neuroblast QL, encodes a member of the Wnt family of secreted glycoproteins. We have found that a second Wnt pathway gene, bar-1, which encodes a beta-catenin/Armadillo-like protein, is also required for activation of mab-5 expression in QL. In addition, we describe the gene pry-1, which is required to limit expression of the Hox genes lin-39, mab-5 and egl-5 to their correct local domains. We find that egl-20, pry-1 and bar-1 all function in a linear genetic pathway with conserved Wnt signaling components, suggesting that a conserved Wnt pathway activates expression of mab-5 in the migratory neuroblast QL. Moreover, we find that members of this Wnt signaling system play a major role in both the general and fine-scale control of Hox gene expression in other cell types along the A/P axis.

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