The Wnt pathway: A macrophage effector molecule that triggers inflammation

Pereira, Cláudia; Bächli, Esther; Schoedon, Gabriele

doi:10.1007/s11883-009-0036-4

Cited by 87 publications

(90 citation statements)

References 49 publications

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“…We found enrichment of differentially methylated promoters in the WNT signaling pathway complex with hypomethylation of 15 genes in the abused. Elsewhere this pathway complex has been found to play a key role in embryonic development and cellular proliferation [48], and is deregulated in some chronic health conditions such as obesity [49][50][51], diabetes [52][53][54], metabolic syndrome [55], cancer [56][57][58][59] and inflammatory processes [56][57][58]. Whilst recognizing that our findings do not provide evidence for causal links between child abuse and later outcomes, they nonetheless raise the prospect of mediation by epigenetic modifications.…”

Section: Discussionmentioning

confidence: 66%

Adverse Childhood Experiences and Frequent Insufficient Sleep in 5U.S. States, 2009: A Retrospective Cohort Study

Prock¹

2015

The Societal Burden of Child Abuse

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Background: Childhood abuse is associated with increased adult disease risk, suggesting that processes acting over the long-term, such as epigenetic regulation of gene activity, may be involved. DNA methylation is a critical mechanism in epigenetic regulation. We aimed to establish whether childhood abuse was associated with adult DNA methylation profiles. Methods: In 40 males from the 1958 British Birth Cohort we compared genome-wide promoter DNA methylation in blood taken at 45y for those with, versus those without, childhood abuse (n = 12 vs 28). We analysed the promoter methylation of over 20,000 genes and 489 microRNAs, using MeDIP (methylated DNA immunoprecipitation) in triplicate. Results: We found 997 differentially methylated gene promoters (311 hypermethylated and 686 hypomethylated) in association with childhood abuse and these promoters were enriched for genes involved in key cell signaling pathways related to transcriptional regulation and development. Using bisulfite-pyrosequencing, abuse-associated methylation (MeDIP) at the metalloproteinase gene, PM20D1, was validated and then replicated in an additional 27 males. Abuse-associated methylation was observed in 39 microRNAs; in 6 of these, the hypermethylated state was consistent with the hypomethylation of their downstream gene targets. Although distributed across the genome, the differentially methylated promoters associated with child abuse clustered in genome regions of at least one megabase. The observations for child abuse showed little overlap with methylation patterns associated with socioeconomic position. Conclusions: Our observed genome-wide methylation profiles in adult DNA associated with childhood abuse justify the further exploration of epigenetic regulation as a mediating mechanism for long-term health outcomes.

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Section: Discussionmentioning

confidence: 66%

Adverse Childhood Experiences and Frequent Insufficient Sleep in 5U.S. States, 2009: A Retrospective Cohort Study

Prock¹

2015

The Societal Burden of Child Abuse

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“…Wnt5a is also associated with macrophage inflammatory responses (35) and plaque instability (36). Thus, the increase in Wnt5a levels in advanced lesions could be an attempt to block intracellular cholesterol accumulation, and this might ultimately lead to the deleterious effect of calcifying the lesions.…”

Section: Discussionmentioning

confidence: 99%

Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation

Asmar

Terrand

Jenty

et al. 2016

Journal of Biological Chemistry

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The low density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitously expressed cell surface receptor that protects from intracellular cholesterol accumulation. However, the underlying mechanisms are unknown. Here we show that the extracellular (␣) chain of LRP1 mediates TGF␤-induced enhancement of Wnt5a, which limits intracellular cholesterol accumulation by inhibiting cholesterol biosynthesis and by promoting cholesterol export. Moreover, we demonstrate that the cytoplasmic (␤) chain of LRP1 suffices to limit cholesterol accumulation in LRP1؊/؊ cells. Cholesterol is a major component of mammalian cell membranes that accumulates in the vascular wall during atherosclerosis, the leading cause of death in industrialized societies (1, 2). The low density lipoprotein receptor-related protein 1 (LRP1), 3 a cell surface receptor that belongs to the LDL receptor family, endocytoses multiple ligands (3). It consists of an 85-kDa membrane-bound carboxyl fragment (␤ chain) and a non-covalently attached 515-kDa (␣ chain) amino-terminal fragment (4). We previously demonstrated that LRP1 limits cholesterol accumulation in the arterial wall. Mice deficient for LRP1 in vascular smooth muscle cells (vSMCs) (smLRP1 mice) develop vSMCs proliferation, cholesterol accumulation (5), and massive foam cell formation when fed a cholesterol-rich diet (6 -10). Whereas LRP1 integrates the platelet-derived growth factor (PDGF-BB) (8, 9) and transforming growth factor-␤ (TGF-␤) at the plasma membrane, two pathways known to regulate vSMCs proliferation (7), the physiological importance and function of LRP1 in regulating intracellular cholesterol homeostasis is still poorly understood. Several mechanisms have been proposed. LRP1 has been shown to promote cholesterol export in vSMCs through induction of ATP binding cassette transporter A1 (ABCA1) levels (5) and to induce a Wnt5a/␤-catenin pathway to limit cholesterol overload in mouse embryonic fibroblasts (11). Moreover, smLRP1 mice express very low levels of Wnt5a in vSMCs (12). TGF-␤ also stimulates a non-canonical Wnt5a pathway in airway smooth muscle cells (13). These data strongly suggest that a TGF-␤/LRP1/Wnt5a pathway limits intracellular cholesterol accumulation.How Wnt5a interferes with cholesterol homeostasis is unknown. It might increase cholesterol export and/or block cholesterol synthesis. ABCA1 and the ATP binding cassette transporter G1 (ABCG1) are two proteins that promote cholesterol efflux. Cholesterol synthesis is tightly regulated by a feedback system that senses the level of cholesterol and modulates the transcription of genes encoding enzymes of cholesterol biosynthesis and uptake (14, 15). For instance, when cholesterol levels rise in cells, the membrane-embedded protein of the endoplasmic reticulum (ER), Scap, senses the increase and binds to Insigs, proteins located to the ER. Insigs then limit cleavage and nuclear translocation of sterol regulatory element-binding proteins (SREBPs), in particular SREBP-2, an activator of cholesterol synthesis in liver and a...

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“…Increased serum level of miR-29a for patients with active pulmonary TB versus healthy controls, with sensitivity of 83% and specificity of 80%, respectively. (12,22). A recent study showed that miR-29a was specifically upregulated after the mycobacterial infection of human macrophages (24).…”

Section: Vol 49 2011 Circulating Mirnas In Tuberculosis 4249mentioning

confidence: 99%

Circulating MicroRNAs in Patients with Active Pulmonary Tuberculosis

et al. 2011

J Clin Microbiol

222

179

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Emerging evidence shows that microRNAs (miRNAs) play an important role in pathogen-host interactions. Circulating miRNAs have been repeatedly and stably detected in blood and hold promise to serve as molecular markers for diverse physiological and pathological conditions. To date, the relationship between circulating miRNAs and active pulmonary tuberculosis (TB) has not been reported. Using microarray-based expression profiling followed by real-time quantitative PCR validation, the levels of circulating miRNAs were compared between patients with active pulmonary tuberculosis and matched healthy controls. The receiver operating characteristic curve was used to evaluate the diagnostic effect of selected miRNA. Bioinformatic analysis was used to explore the potential roles of these circulating miRNAs in active pulmonary tuberculosis infection. Among 92 miRNAs significantly detected, 59 miRNAs were downregulated and 33 miRNAs were upregulated in the TB serum compared to their levels in the control serum. Interestingly, only two differentially expressed miRNAs were increased not only in the serum but also in the sputum of patients with active pulmonary tuberculosis compared to the levels for the healthy controls. Upregulated miR-29a could discriminate TB patients from healthy controls with reasonable sensitivity and specificity. A number of significantly enriched pathways regulated by these circulating miRNAs were predicted, and most of them were involved in acutephase response, inflammatory response, and the regulation of the cytoskeleton. In all, for the first time our results revealed that a number of miRNAs were differentially expressed during active pulmonary tuberculosis infection, and circulating miR-29a has great potential to serve as a marker for the detection of active pulmonary tuberculosis infection.

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The Wnt pathway: A macrophage effector molecule that triggers inflammation

Cited by 87 publications

References 49 publications

Adverse Childhood Experiences and Frequent Insufficient Sleep in 5U.S. States, 2009: A Retrospective Cohort Study

Adverse Childhood Experiences and Frequent Insufficient Sleep in 5U.S. States, 2009: A Retrospective Cohort Study

Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation

Circulating MicroRNAs in Patients with Active Pulmonary Tuberculosis

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