Wnt Pathway
2008; Lippincott Williams & Wilkins; Volume: 28; Issue: 3 Linguagem: Suaíli
10.1161/atvbaha.107.160952
ISSN1524-4636
Autores Tópico(s)Epigenetics and DNA Methylation
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 28, No. 3Wnt Pathway Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWnt PathwayA New Role in Regulation of Inflammation Sarah Jane George Sarah Jane GeorgeSarah Jane George From the Bristol Heart Institute, Bristol Royal Infirmary, UK. Originally published1 Mar 2008https://doi.org/10.1161/ATVBAHA.107.160952Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:400–402The Wnt pathway plays a critical role in the development of multicellular organisms.1,2 It shows evolutionary conservation across a wide range of species, ranging from the freshwater polyp Hydra to worms, flies, and vertebrates. Since the 1980s our knowledge of Wnt signal transduction has expanded tremendously. This family of proteins comprises a group of 19 secreted lipid-modified glycoproteins that not only play a crucial role in the regulation of embryogenesis and development but also cell proliferation, differentiation, polarity, migration, and invasion.1,2 Abnormal Wnt signaling has been associated with many human diseases, ranging from cancer to degenerative diseases. Thus studies of Wnt signaling have opened up new avenues in biomedical research, including molecular embryology, stem cell biology, tumorigenesis, regenerative medicine, and rational drug discovery.3 Interestingly, in this issue of Arteriosclerosis Thrombosis and Vascular Biology, Pereira and colleagues highlight the involvement of the Wnt pathway in the sustained inflammation in sepsis. This study contributes to the accumulating evidence that the Wnt pathway also plays a distinct role in inflammation and immunity.See accompanying article on page 504Pereira and colleagues suggest that Wnt5a is a highly specific autocrine and paracrine macrophage-derived effector molecule which triggers inflammation. Altered macrophage functions contribute to the pathogenesis of many infectious, immunologic, and inflammatory disease processes in addition to sepsis, such as rheumatoid arthritis and atherosclerosis. Development of novel pharmacological modulators of macrophage activity represents an important strategy for the prevention and treatment of these inflammation-related diseases. Consequently the findings of Pereira and colleagues may have wider impact by relevance to other pathological conditions which involve inflammation. Additionally these findings indicate that Wnt5a is an attractive candidate for therapeutic intervention in inflammatory diseases.Genomic studies have detected upregulation of Wnt5a in macrophages and dendritic cells exposed to pathogens4,5 and during differentiation of monocytes into dendritic cells after exposure to GM-colony stimulating factor (CSF) and interleukin (IL)-4.6 Together, this suggests that Wnt5a expression contributes to innate and adaptive immune responses. In support of this, upregulation of Wnt5a has been observed in pathological conditions involving inflammation such as rheumatoid arthritis7 and in tumor associated macrophages.8 One of the first direct indicators for the involvement of the Wnt pathway in inflammation and immunity was obtained from a study in Drosophila. Gordon and colleagues illustrated that the Drosophila Wnt protein family member WntD is upregulated in the fly via Toll/nuclear factor-κB (NF-κB) signaling and is involved in the innate immune system.9 A subsequent study in human mononuclear cells demonstrated upregulation of Wnt5a in response to microbial stimulation required Toll/NF-κB activation, indicating a similar mechanism in man.10 Interestingly, this study also demonstrated that Wnt5a upregulates the microbially-induced IL-12 response of antigen-presenting cells and IFN-γ production by mycobacterial antigen-stimulated T-cells, illustrating a functional involvement in the antimicrobial defense.10 This was the first implication of the involvement of Wnt signaling in bridging innate and adaptive immunity to infections. In this recent study by Pereira and colleagues utilizing an in vitro model of inflammatory macrophage activation, additional support for a role of Wnt5a in sustained macrophage activation is provided. Macrophages stimulated with interferon (INF)-γ and endotoxin (LPS) consistently upregulated Wnt5a via Toll-like receptor activation. Wnt5a in turn upregulated expression of the proinflammatory genes, IL-6, IL-1β, IL-8, and macrophage inflammatory protein-1β (MIP-1β). Attenuation of these effects by activated protein C (APC) and the antiinflammatory cytokine IL-10 imply an active role of Wnt5a in the inflammatory response. Although these findings are not the first demonstration that Wnt5a regulates macrophage activation, this study is the first to provide a direct demonstration of relevance to pathological inflammation by showing higher levels of Wnt5a in patients with severe sepsis than healthy subjects.Membership in the Wnt family is defined by amino acid sequence rather than functional properties. It is therefore not surprising that Wnts are associated with a number of different activities and downstream signaling pathways. The intracellular responses triggered by Wnts binding to their receptors, the Frizzled family of proteins, and activation of the key intermediate Dishevelled, are classified as canonical and noncanonical.11 The canonical signaling blocks degradation of cytosolic β-catenin and hence activates β-catenin/TCF transcriptional responses. This pathway is well characterized and involves the inhibition of glycogen synthase kinase-3β (GSK-3β) activity, translocation of β-catenin to the nucleus, and binding to nuclear transcription factor T cell factor (TCF).12 As a consequence it is responsible for the regulation of more than 50 mammalian genes. Initially, noncanonical signaling which is less well-defined was primarily associated with modulation of cell movement. It is β-catenin independent and activates the Wnt/Ca2+ and Wnt/planar cell polarity pathways. Evidence in flies and vertebrates points toward a complete separation of the canonical and noncanonical pathways downstream of Dishevelled.12 Noncanonical Wnts cause intracellular calcium flux leading to activation of Ca2+-dependent effector molecules such as calcium/calmodulin dependent kinase II (CamKII), nuclear factor associated with T cells (NFAT), and proteins kinase C (PKC) in a pertussis toxin (PTX)-sensitive manner. Because NFAT is associated with regulation of various genes including cytokines, cell cycle, differentiation, and apoptosis,13 the noncanonical pathway can modulate cell behavior via gene transcription.Pereira and colleagues illustrate that Wnt5a activates CaMKII noncanonical signaling. Although not shown in this article, CAMKII activation may result in the activation of NFAT-dependent transcription as observed previously6 and lead thereby to the observed upregulation of cytokine expression. This study has raised awareness of the potential involvement of activation of noncanonical signaling via Wnt5a in inflammation. However, it appears this may only be the tip of the iceberg. Despite its classification as a noncanonical Wnt, recent evidence suggests that Wnt5a can also activate or inhibit canonical signaling depending on the receptor context.14 The ability of canonical signaling to upregulate the expression of several Wnt/β-catenin responsive genes in monocytes has raised the possibility that this pathway may also contribute to inflammation.15 Future studies are required, however, to provide direct information on the contribution of canonical signaling to the inflammatory response. Additionally, these initial studies have focused on Wnt5a, and there may be further involvement of this pathway via other Wnt proteins. Finally, it is highly probable that expression of Wnts from macrophages and dendritic cells has numerous affects on the behavior of the resident tissue cells via activation of canonical or noncanonical signaling. For example, cell death,16,17 proliferation,17–21 migration,21 and invasion22 of cell types adjacent to the macrophage including vascular smooth muscle cells and endothelial cells may also be affected by increased release of Wnt proteins by macrophages.In summary our current knowledge strongly supports the involvement of Wnt5a signaling in the inflammatory response (see Figure). There is substantial evidence for the upregulation of Wnt5a by pathogens which leads to activation of noncanonical signaling in macrophages. It is likely, however, that future studies will reveal a more extensive role of this pathway in inflammatory diseases. A greater understanding of the modulators of Wnt expression and the noncanonical and canonical effects of Wnt proteins on inflammatory and resident cells will be paramount to clarifying the role of this pathway and perhaps enable the design of novel anti-inflammatory treatments. Download figureDownload PowerPointFigure. Working hypothesis of the role of Wnt5a in the inflammatory response. Activation of Toll-like receptors in macrophages by pathogens leads to activation of nuclear factor-κB (NF-κB) and upregulation of Wnt5a and cytokines. Increased levels of Wnt5a activate the noncanonical pathway via calcium/calmodulin dependent kinase II (CAMKII) which results in sustained upregulation of inflammatory cytokines including IL-12, IL-6, IL-8, IL-1β, and macrophage inflammatory protein-1β (MIP-1β) either in a nuclear factor of activated T-cells (NFAT)-dependent or independent manner. Additionally, increased levels of Wnt5a and cytokines may affect other mononuclear cells including T-cells and surrounding resident tissue cells.DisclosuresNone.FootnotesCorrespondence to Sarah Jane George, Bristol Heart Institute, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom. E-mail [email protected] References 1 Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Ann Rev Cell Dev Biol. 2004; 20: 781–810.CrossrefMedlineGoogle Scholar2 Clevers H. Wnt/β-catenin signaling in development and disease. Cell. 2006; 127: 469–480.CrossrefMedlineGoogle Scholar3 Moon RT, Kohn AD, De Ferrari GV, Kaykas A. Wnt and β-catenin signalling: diseases and therapies. Nature Rev Genetics. 2004; 5: 689–699.Google Scholar4 Chaussabel D, Semnani RT, McDowell MA, Sacks D, Sher A, Nutman TB. Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites. Blood. 2003; 102: 672–681.CrossrefMedlineGoogle Scholar5 Nau GJ, Richmond JFL, Schlesinger A, Jennings EG, Lander ES, Young RA. Human macrophage activation programs induced by bacterial pathogens. Proc Natl Acad Sci U S A. 2002; 99: 1503–1508.CrossrefMedlineGoogle Scholar6 Lehtonen A, Ahlfors H, Veckman V, Miettinen M, Lahesmaa R, Julkunen I. Gene expression profiling during differentiation of human monocytes to macrophages or dendritic cells. J Leukoc Biol. 2007; 82: 710–720.CrossrefMedlineGoogle Scholar7 Sen M, Lauterbach K, El-Gabalawy H, Firestein GS, Corr M, Carson DA. Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000; 97: 2791–2796.CrossrefMedlineGoogle Scholar8 Smith K, Bui TD, Poulsom R, Kaklamanis L, Williams G, Harris AL. Up-regulation of macrophage wnt gene expression in adenoma-carcinoma progression of huma colorectal cancer. Br J Cancer. 1999; 81: 496–502.CrossrefMedlineGoogle Scholar9 Gordon MD, Dionne MS, Schneider DS, Nusse R. WntD is a feedback inhibitor of Dorsal/NF-κB in Drosophila development and immunity. Nature. 2005; 437: 746.CrossrefMedlineGoogle Scholar10 Blumenthal A, Ehlers S, Lauber J, Buer J, Lange C, Goldmann T, Heine H, Brandt E, Reiling N. The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation. Blood. 2006; 108: 965–973.CrossrefMedlineGoogle Scholar11 Schulte G, Bryja V. The Frizzled family of unconventional G-protein-coupled receptors. Trends Pharm Sci. 2007; 28: 518.CrossrefMedlineGoogle Scholar12 Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem. 2006; 281: 22429–22433.CrossrefMedlineGoogle Scholar13 Viola JPB, Carvalho LDS, Fonseca BPF, Teixeira LK. NFAT transcription factors: from cell cycle to tumor development. Braz J Med Biol Res. 2005; 38: 335–344.CrossrefMedlineGoogle Scholar14 Mikels AJ, Nusse R. Purified Wnt5a protein activates or inhibits β-catenin-TCF signaling depending on receptor context. PLos Biology. 2006; 4: e115.CrossrefMedlineGoogle Scholar15 Thiele A, Wasner M, Muller C, Engeland K, Hauschildt S. Regulation and possible function of beta-catenin in human monocytes. J Immunol. 2001; 167: 6786–6793.CrossrefMedlineGoogle Scholar16 Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M, Ondr JK, Kurup S, Glass DA, Patel MS, Shu WG, Morrisey EE, McMahon AP, Karsenty G, Lang RA. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature. 2005; 437: 417–421.CrossrefMedlineGoogle Scholar17 Masckauchan TNH, Agalliu D, Vorontchikhina M, Ahn A, Parmalee NL, Li C-M, Khoo A, Tycko B, Brown AMC, Kitajewski J. Wnt5a Signaling Induces Proliferation and Survival of Endothelial Cells In Vitro and Expression of MMP-1 and Tie-2. Mol Biol Cell. 2006; 17: 5163–5172.CrossrefMedlineGoogle Scholar18 Quasnichka H, Slater SC, Beeching CA, Boehm M, Sala-Newby GB, George SJ. Regulation of smooth muscle cell proliferation by β-catenin/TCF signaling involves modulation of cyclin D1 and p21 expression. Circ Res. 2006; 99: 1329–1337.LinkGoogle Scholar19 Wang X, Xiao Y, Mou Y, Zhao Y, Blankesteijn M, Hall JL. A role for the β-catenin/T-cell factor signaling cascade in vascular remodeling. Circ Res. 2002; 90: 340–347.CrossrefMedlineGoogle Scholar20 Wang X, Adhikari N, Li Q, Hall JL. The LDL receptor related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol. 2004; 287: H2376–H2383.CrossrefMedlineGoogle Scholar21 Cheng C-w, Yeh J-c, Fan T-P, Smith SK, Charnock-Jones DS. Wnt5a-mediated non-canonical Wnt signalling regulates human endothelial cell proliferation and migration. Biochem Biophys Res Comm. 2007; 365: 285–290.MedlineGoogle Scholar22 Pukrop T, Klemm F, Hagemann T, Gradl D, Schulz M, Siemes S, Trumper L, Binder C. Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. Proc Natl Acad Sci U S A. 2006; 103: 5454–5459.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Lu Y, Liu M, Guo X, Wang P, Zeng F, Wang H, Tang J, Qin Z and Tao T (2023) miR‐26a‐5p alleviates CFA‐induced chronic inflammatory hyperalgesia through Wnt5a/CaMKII/NFAT signaling in mice, CNS Neuroscience & Therapeutics, 10.1111/cns.14099 Yuan L, Tang Y, Yin L, Lin X, Luo Z, Wang S, Li J, Liang P and Jiang B (2022) Microarray Analysis Reveals Changes in tRNA-Derived Small RNAs (tsRNAs) Expression in Mice with Septic Cardiomyopathy, Genes, 10.3390/genes13122258, 13:12, (2258) Avery D, Morandini L, Sheakley L, Shah A, Bui L, Abaricia J and Olivares-Navarrete R (2022) Canonical Wnt signaling enhances pro-inflammatory response to titanium by macrophages, Biomaterials, 10.1016/j.biomaterials.2022.121797, 289, (121797), Online publication date: 1-Oct-2022. VanValkenburg A, Kaipilyawar V, Sarkar S, Lakshminarayanan S, Cintron C, Prakash Babu S, Knudsen S, Joseph N, Horsburgh C, Sinha P, Ellner J, Narasimhan P, Johnson W, Hochberg N and Salgame P (2022) Malnutrition leads to increased inflammation and expression of tuberculosis risk signatures in recently exposed household contacts of pulmonary tuberculosis, Frontiers in Immunology, 10.3389/fimmu.2022.1011166, 13 Ji X, Fan Y, Sun F, Wang J and Wang K (2022) Noncanonical Wnt5a/JNK Signaling Contributes to the Development of D-Gal/LPS-Induced Acute Liver Failure, Inflammation, 10.1007/s10753-022-01627-y, 45:3, (1362-1373), Online publication date: 1-Jun-2022. Marcelino R, Cardoso R, Domingues E, Gonçalves R, Lima G and Novaes R (2022) The emerging risk of microplastics and nanoplastics on the microstructure and function of reproductive organs in mammals: A systematic review of preclinical evidence, Life Sciences, 10.1016/j.lfs.2022.120404, 295, (120404), Online publication date: 1-Apr-2022. Hsu Y, Huang K and Cheng K (2021) Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology, Advanced Biology, 10.1002/adbi.202101133, 6:2, (2101133), Online publication date: 1-Feb-2022. Zhang M, Yang D, Yu H and Li Q (2021) MicroRNA-497 inhibits inflammation in DSS-induced IBD model mice and lipopolysaccharide-induced RAW264.7 cells via Wnt/β-catenin pathway, International Immunopharmacology, 10.1016/j.intimp.2021.108318, 101, (108318), Online publication date: 1-Dec-2021. Deutschman C, Hellman J, Roca R, De Backer D, Coopersmith C, Coopersmith C, De Backer D, Antonelli M, Deutschman C, Evans L, Ferrer-Roca R, Hellman J, Jog S, Kesecioglu J, Lat I, Levy M, Machado F, Martin G, Martin-Loeches I, Nunnally M and Rhodes A (2020) The surviving sepsis campaign: basic/translational science research priorities, Intensive Care Medicine Experimental, 10.1186/s40635-020-00312-4, 8:1, Online publication date: 1-Dec-2020. Yu T, Dong D, Guan J, Sun J, Guo M and Wang Q (2019) Alprostadil attenuates LPS-induced cardiomyocyte injury by inhibiting the Wnt5a/JNK/NF-κB pathwayAlprostadil schwächt LPS-induzierte Kardiomyozytenschädigung durch Hemmung des Wnt5a/JNK/NF-κB-Signalwegs ab, Herz, 10.1007/s00059-019-4837-0, 45:S1, (130-138), Online publication date: 1-Dec-2020. Shin J, Yoon Y and Oh D (2020) Evaluation of the Wnt signaling pathway as a prognostic marker in patients with urosepsis, Molecular and Cellular Biochemistry, 10.1007/s11010-020-03804-9, 473:1-2, (15-23), Online publication date: 1-Oct-2020. Deutschman C, Hellman J, Ferrer Roca R, De Backer D and Coopersmith C (2020) The Surviving Sepsis Campaign: Basic/Translational Science Research Priorities*, Critical Care Medicine, 10.1097/CCM.0000000000004408, 48:8, (1217-1232), Online publication date: 1-Aug-2020. Rao J, Yang C, Yang S, Lu H, Hu Y, Lu L, Cheng F and Wang X (2020) Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex, International Immunology, 10.1093/intimm/dxaa002, 32:5, (321-334), Online publication date: 8-May-2020. Resham K and Sharma S (2019) Pharmacological interventions targeting Wnt/β-catenin signaling pathway attenuate paclitaxel-induced peripheral neuropathy, European Journal of Pharmacology, 10.1016/j.ejphar.2019.172714, 864, (172714), Online publication date: 1-Dec-2019. Ljungberg J, Kling J, Tran T and Blumenthal A (2019) Functions of the WNT Signaling Network in Shaping Host Responses to Infection, Frontiers in Immunology, 10.3389/fimmu.2019.02521, 10 Xu Y, Wang Q, Wu Z, Lu K, Cheng X, Jin W and Zhao Y (2019) The effect of lithium chloride on the attenuation of cognitive impairment in experimental hypoglycemic rats, Brain Research Bulletin, 10.1016/j.brainresbull.2019.04.019, 149, (168-174), Online publication date: 1-Jul-2019. Wang C, Yu T, Wu C, Hung W, Hsu C, Tsai I, Tang W, Chung F, Houng J, Lee Y and Lu Y (2018) Circulating secreted frizzled-related protein 5 and chronic kidney disease in patients with acute ST-segment elevation myocardial infarction, Cytokine, 10.1016/j.cyto.2018.04.009, 110, (367-373), Online publication date: 1-Oct-2018. Wong D, Yiu W, Chan K, Li Y, Li B, Lok S, Taketo M, Igarashi P, Chan L, Leung J, Lai K and Tang S (2018) Activated renal tubular Wnt/β-catenin signaling triggers renal inflammation during overload proteinuria, Kidney International, 10.1016/j.kint.2017.12.017, 93:6, (1367-1383), Online publication date: 1-Jun-2018. Chhetri J, de Souto Barreto P, Fougère B, Rolland Y, Vellas B and Cesari M (2018) Chronic inflammation and sarcopenia: A regenerative cell therapy perspective, Experimental Gerontology, 10.1016/j.exger.2017.12.023, 103, (115-123), Online publication date: 1-Mar-2018. Chen Z, Han S, Shi M, Liu G, Chen Z, Chang J, Wu C and Xiao Y (2018) Immunomodulatory effects of mesoporous silica nanoparticles on osteogenesis: From nanoimmunotoxicity to nanoimmunotherapy, Applied Materials Today, 10.1016/j.apmt.2017.12.003, 10, (184-193), Online publication date: 1-Mar-2018. Albanese I, Khan K, Barratt B, Al‐Kindi H and Schwertani A (2018) Atherosclerotic Calcification: Wnt Is the Hint, Journal of the American Heart Association, 7:4, Online publication date: 20-Feb-2018. Wang W, Liu M, Wang Y, Yang T, Li D, Ding F, Sun H, Bai G and Li Q (2018) Lycium barbarum Polysaccharide Promotes Maturation of Dendritic Cell via Notch Signaling and Strengthens Dendritic Cell Mediated T Lymphocyte Cytotoxicity on Colon Cancer Cell CT26-WT , Evidence-Based Complementary and Alternative Medicine, 10.1155/2018/2305683, 2018, (1-10), . Fang Y, Kang Y, Zou H, Cheng X, Xie T, Shi L and Zhang H (2018) β-elemene attenuates macrophage activation and proinflammatory factor production via crosstalk with Wnt/β-catenin signaling pathway, Fitoterapia, 10.1016/j.fitote.2017.10.015, 124, (92-102), Online publication date: 1-Jan-2018. Zhou L, Dörfer C, Chen L and Fawzy El-Sayed K (2017) Porphyromonas gingivalis lipopolysaccharides affect gingival stem/progenitor cells attributes through NF-κB, but not Wnt/β-catenin, pathway , Journal of Clinical Periodontology, 10.1111/jcpe.12777, 44:11, (1112-1122), Online publication date: 1-Nov-2017. Sharma A, Yang W, Ochani M and Wang P (2017) Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling, Scientific Reports, 10.1038/s41598-017-08711-6, 7:1 Farnoodian M, Wang S, Dietz J, Nickells R, Sorenson C and Sheibani N (2017) Negative regulators of angiogenesis: important targets for treatment of exudative AMD, Clinical Science, 10.1042/CS20170066, 131:15, (1763-1780), Online publication date: 1-Aug-2017. Wu T, Zhang J, Geng M, Tang S, Zhang W and Shu J (2017) Nucleoside reverse transcriptase inhibitors (NRTIs) induce proinflammatory cytokines in the CNS via Wnt5a signaling, Scientific Reports, 10.1038/s41598-017-03446-w, 7:1 Sun X, Chen L and Yan W (2017) TIPE2 Inhibits the Expression of Asthma-Related Inflammatory Factors in Hyperstretched Bronchial Epithelial Cells Through the Wnt/β-Catenin Pathway, Inflammation, 10.1007/s10753-017-0521-9, 40:3, (770-777), Online publication date: 1-Jun-2017. Maekawa T, Kulwattanaporn P, Hosur K, Domon H, Oda M, Terao Y, Maeda T and Hajishengallis G (2017) Differential Expression and Roles of Secreted Frizzled-Related Protein 5 and the Wingless Homolog Wnt5a in Periodontitis, Journal of Dental Research, 10.1177/0022034516687248, 96:5, (571-577), Online publication date: 1-May-2017. Han Z, Xu Q, Li C and Zhao H (2017) Effects of sulforaphane on neural stem cell proliferation and differentiation, genesis, 10.1002/dvg.23022, 55:3, (e23022), Online publication date: 1-Mar-2017. Utomo W, de Vries M, Braat H, Bruno M, Parikh K, Comalada M, Peppelenbosch M, van Goor H and Fuhler G (2017) Modulation of Human Peripheral Blood Mononuclear Cell Signaling by Medicinal Cannabinoids, Frontiers in Molecular Neuroscience, 10.3389/fnmol.2017.00014, 10 Palevski D, Levin‐Kotler L, Kain D, Naftali‐Shani N, Landa N, Ben‐Mordechai T, Konfino T, Holbova R, Molotski N, Rosin‐Arbesfeld R, Lang R and Leor J (2017) Loss of Macrophage Wnt Secretion Improves Remodeling and Function After Myocardial Infarction in Mice, Journal of the American Heart Association, 6:1, Online publication date: 11-Jan-2017. Skaria T, Bachli E and Schoedon G (2016) Wnt5A/Ryk signaling critically affects barrier function in human vascular endothelial cells, Cell Adhesion & Migration, 10.1080/19336918.2016.1178449, 11:1, (24-38), Online publication date: 2-Jan-2017. Brandenburg J and Reiling N (2016) The Wnt Blows: On the Functional Role of Wnt Signaling in Mycobacterium tuberculosis Infection and Beyond, Frontiers in Immunology, 10.3389/fimmu.2016.00635, 7 Undi R, Sarvothaman S, Narasaiah K, Gutti U and Gutti R (2016) Toll-like receptor 2 signalling: Significance in megakaryocyte development through wnt signalling cross-talk and cytokine induction, Cytokine, 10.1016/j.cyto.2016.05.007, 83, (245-249), Online publication date: 1-Jul-2016. Luo T, Dunphy P, Lina T, McBride J and Palmer G (2016) Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival, Infection and Immunity, 10.1128/IAI.01289-15, 84:3, (686-700), Online publication date: 1-Mar-2016. Zhang J, Rane G, Dai X, Shanmugam M, Arfuso F, Samy R, Lai M, Kappei D, Kumar A and Sethi G (2016) Ageing and the telomere connection: An intimate relationship with inflammation, Ageing Research Reviews, 10.1016/j.arr.2015.11.006, 25, (55-69), Online publication date: 1-Jan-2016. MA Y, YANG Y, SUN W, ZHOU R, LI K and TANG Z (2016) SFRP2 affects prenatal muscle development and is regulated by microRNA-1/206 in pigs, Journal of Integrative Agriculture, 10.1016/S2095-3119(14)60917-5, 15:1, (153-161), Online publication date: 1-Jan-2016. Kwak H, Park D, Seo J, Moon J, Kim T, Sohn J, Shin D, Yoon H, Park S and Kim S (2015) The Wnt/β-catenin signaling pathway regulates the development of airway remodeling in patients with asthma, Experimental & Molecular Medicine, 10.1038/emm.2015.91, 47:12, (e198-e198) Nie W, Lv Y, Yan L, Chen X and Lv H (2015) Prediction and Characterisation of the System Effects of Aristolochic Acid: A Novel Joint Network Analysis towards Therapeutic and Toxicological Mechanisms, Scientific Reports, 10.1038/srep17646, 5:1 Martini M, Capodimonti S, Iachininoto M, Cocomazzi A, Nuzzolo E, Voso M, Teofili L and Larocca L (2015) An abnormal secretion of soluble mediators contributes to the hematopoietic-niche dysfunction in low-risk myelodysplastic syndrome, Blood Cancer Journal, 10.1038/bcj.2015.97, 5:11, (e370-e370), Online publication date: 1-Nov-2015. Takahashi Y, Chen Q, Rajala R and Ma J (2015) MicroRNA-184 modulates canonical Wnt signaling through the regulation of frizzled-7 expression in the retina with ischemia-induced neovascularization, FEBS Letters, 10.1016/j.febslet.2015.03.010, 589:10, (1143-1149), Online publication date: 28-Apr-2015. Qi W, Yang C, Dai Z, Che D, Feng J, Mao Y, Cheng R, Wang Z, He X, Zhou T, Gu X, Yan L, Yang X, Ma J and Gao G (2014) High Levels of Pigment Epithelium–Derived Factor in Diabetes Impair Wound Healing Through Suppression of Wnt Signaling, Diabetes, 10.2337/db14-1111, 64:4, (1407-1419), Online publication date: 1-Apr-2015. Ji X, Li X, Fan Y, Zhao Z, Gao S, Sun F, Zhao J and Wang K (2014) Serum wnt5a is a predictor for the prognosis of acute on chronic hepatitis B liver failure, Biomarkers, 10.3109/1354750X.2014.986196, 20:1, (26-34), Online publication date: 2-Jan-2015. Tan X, Wang X, Chu H, Liu H, Yi X and Xiao Y (2013) SFRP5 correlates with obesity and metabolic syndrome and increases after weight loss in children, Clinical Endocrinology, 10.1111/cen.12361, 81:3, (363-369), Online publication date: 1-Sep-2014. McBride J, Jenkins A, Liu X, Zhang B, Lee K, Berry W, Janknecht R, Griffin C, Aston C, Lyons T, Tomasek J and Ma J (2014) Elevated Circulation Levels of an Antiangiogenic SERPIN in Patients with Diabetic Microvascular Complications Impair Wound Healing through Suppression of Wnt Signaling, Journal of Investigative Dermatology, 10.1038/jid.2014.40, 134:6, (1725-1734), Online publication date: 1-Jun-2014. Deb A (2014) Cell-cell interaction in the heart via Wnt/ -catenin pathway after cardiac injury, Cardiovascular Research, 10.1093/cvr/cvu054, 102:2, (214-223), Online publication date: 1-May-2014. Malgor R, Bhatt P, Connolly B, Jacoby D, Feldmann K, Silver M, Nakazawa M, McCall K and Goetz D (2013) Wnt5a, TLR2 and TLR4 are elevated in advanced human atherosclerotic lesions, Inflammation Research, 10.1007/s00011-013-0697-x, 63:4, (277-285), Online publication date: 1-Apr-2014. Tzanno-Martins C, Biavo B, Ferreira-Filho O, Ribeiro-Junior E, João-Luiz M, Degaspari S, Scavone C and Kawamoto E (2014) Clinical Efficacy, Safety and Anti-Inflammatory Activity of Two Sevelamer Tablet Forms in Patients on Low-Flux Hemodialysis, International Journal of Immunopathology and Pharmacology, 10.1177/039463201402700105, 27:1, (25-35), Online publication date: 1-Jan-2014. Wang J, Dai J, Liu B, Gu S, Cheng L and Liang J (2013) Porphyromonas gingivalis Lipopolysaccharide Activates Canonical Wnt/β-Catenin and p38 MAPK Signalling in Stem Cells from the Apical Papilla, Inflammation, 10.1007/s10753-013-9679-y, 36:6, (1393-1402), Online publication date: 1-Dec-2013. Chandrakesan P, Jakkula L, Ahmed I, Roy B, Anant S, Umar S and Liu C (2013) Differential Effects of β-catenin and NF-κB Interplay in the Regulation of Cell Proliferation, Inflammation and Tumorigenesis in Response to Bacterial Infection, PLoS ONE, 10.1371/journal.pone.0079432, 8:11, (e79432) Pandey S and Chandravati (2013) Targeting Wnt-Frizzled signaling in cardiovascular diseases, Molecular Biology Reports, 10.1007/s11033-013-2710-4, 40:10, (6011-6018), Online publication date: 1-Oct-2013. Al-Chaqmaqchi H, Moshfegh A, Dadfar E, Paulsson J, Hassan M, Jacobson S, Lundahl J and Mo
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