Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Skokos, Eleni A.; Charokopos, Antonios; Khan, Khadija; Wanjala, Jackie; Kyriakides, Themis R.

doi:10.1016/j.ajpath.2011.01.045

Cited by 56 publications

(80 citation statements)

References 47 publications

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“…Cadherins help to maintain blood vessel integrity (5). MMP-9 has been reported to downregulate cadherins through proteolytic shedding, which would increase vascular permeability (9,32). The absence of a similar increase of Cdh1 in the Null mice suggests that the increase in the WT may be a compensatory mechanism to improve impaired vascular permeability.…”

Section: Discussionmentioning

confidence: 86%

Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction

Yabluchanskiy

Chiao

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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. Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction. Am J Physiol Heart Circ Physiol 306: H1398 -H1407, 2014. First published March 21, 2014; doi:10.1152/ajpheart.00090.2014Aging is linked to increased matrix metalloproteinase-9 (MMP-9) expression and extracellular matrix turnover, as well as a decline in function of the left ventricle (LV). Previously, we demonstrated that C57BL/6J wild-type (WT) mice Ͼ 18 mo of age show impaired diastolic function, which was attenuated by MMP-9 deletion. To evaluate mechanisms that initiate the development of cardiac dysfunction, we compared the LVs of 6 -9-and 15-18-mo-old WT and MMP-9 null (Null) mice. All groups showed similar LV function by echocardiography, indicating that dysfunction had not yet developed in the older group. Myocyte nuclei numbers and cross-sectional areas increased in both WT and Null 15-18-mo mice compared with young controls, indicating myocyte hypertrophy. Myocyte hypertrophy leads to an increased oxygen demand, and both WT and Null 15-18-mo mice showed an increase in angiogenic signaling. Plasma proteomic profiling and LV analysis revealed a threefold increase in von Willebrand factor and fivefold increase in vascular endothelial growth factor in WT 15-18-mo mice, which were further elevated in Null mice. In contrast to the upregulation of angiogenic stimulating factors, actual LV vessel numbers increased only in the 15-18-mo Null LV. The 15-18-mo WT showed amplified expression of inflammatory genes related to angiogenesis, including C-C chemokine receptor (CCR)7, CCR10, interleukin (IL)-1f8, IL-13, and IL-20 (all, P Ͻ 0.05), and these increases were blunted by MMP-9 deletion (all, P Ͻ 0.05). To measure vascular permeability as an index of endothelial function, we injected mice with FITC-labeled dextran. The 15-18-mo WT LV showed increased vascular permeability compared with young WT controls and 15-18-mo Null mice. Combined, our findings revealed that MMP-9 deletion improves angiogenesis, attenuates inflammation, and prevents vascular leakiness in the setting of cardiac aging.aging; inflammation; angiogenesis; MMP-9; proteomics; extracellular matrix AGING IS A MAJOR RISK FACTOR for cardiac mortality and morbidity (11, 30). Elderly patients with acute cardiovascular disease have poor clinical outcomes. Aging is associated with alterations in homeostatic mechanisms that make the vasculature more susceptible to damaging effects of pathophysiological conditions (35). Aging impairs diastolic function in humans, independent of existing comorbidities such as hypertension (18). In mice, aging associates with a subtle but significant decline in function of the left ventricle (LV) (21). Altered LV function is characterized by the development of diastolic dysfunction, as systolic function remains relatively unchanged (7). The cardiac extracellular matrix (ECM) regulates LV diastolic properties, provides structural support for the myocardium, and incorporates homeostatic elements such as growth factors (16). Matrix metal...

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Section: Discussionmentioning

confidence: 86%

Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction

Yabluchanskiy

Chiao

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Compared with control macrophages, β-catenin-deficient macrophages showed decreased expression of numerous genes with functions attributed to migration and adhesion, including members of the cadherin, integrin, and a disintegrin and metalloproteinase (ADAM) gene families (Gene Expression Omnibus database, GEO GSE52163) (Supplemental Table 2). Cadherins and catenins are important for macrophage cell contact (27)(28)(29)(30)(31), whereas ADAMs and integrins are important for macrophage cell migration (32). More than 50% of ADAM and integrin gene family members showed lower expression levels in macrophages from Lysz-Cre Catnb tm2KEM mice compared with those observed in control macrophages (Supplemental Table 3 and Supplemental Table 4).…”

Section: Lysozyme-expressing Progeny Cells Account For 18% Of Cells Imentioning

confidence: 98%

β-Catenin–regulated myeloid cell adhesion and migration determine wound healing

Amini-Nik¹,

Cambridge²,

Yu³

et al. 2014

J. Clin. Invest.

110

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A β-catenin/T cell factor-dependent transcriptional program is critical during cutaneous wound repair for the regulation of scar size; however, the relative contribution of β-catenin activity and function in specific cell types in the granulation tissue during the healing process is unknown. Here, cell lineage tracing revealed that cells in which β-catenin is transcriptionally active express a gene profile that is characteristic of the myeloid lineage. Mice harboring a macrophage-specific deletion of the gene encoding β-catenin exhibited insufficient skin wound healing due to macrophage-specific defects in migration, adhesion to fibroblasts, and ability to produce TGF-β1. In irradiated mice, only macrophages expressing β-catenin were able to rescue woundhealing deficiency. Evaluation of scar tissue collected from patients with hypertrophic and normal scars revealed a correlation between the number of macrophages within the wound, β-catenin levels, and cellularity. Our data indicate that β-catenin regulates myeloid cell motility and adhesion and that β-catenin-mediated macrophage motility contributes to the number of mesenchymal cells and ultimate scar size following cutaneous injury.

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“…For example, fusion of macrophages results in the formation of multinucleated giant cells (MNGs), which is a typical feature of granulomatous inflammation and foreign body reactions. [94][95][96][97][98] Moreno et al found that IL-4 induces MNG generation in a STAT6-dependent manner by regulating the expression of at least 2 fusion mediators, E-cadherin and DC-STAMP, resulting in homotypic macrophage fusion and engulfment of large foreign bodies. 99 In addition TREM-2 and its signaling association partner DAP12 are required for IL-4-induced E-cadherin and DC-STAMP expression, and giant cell formation in vitro and in vivo.…”

Section: E-cadherin Contributes To Macrophage Fusion and Osteoclastogmentioning

confidence: 99%

Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

Bossche

Malissen

Mantovani

et al. 2012

Blood

139

121

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E-cadherin is best characterized as adherens junction protein, which through homotypic interactions contributes to the maintenance of the epithelial barrier function. In epithelial cells, the cytoplasmic tail of E-cadherin forms a dynamic complex with catenins and regulates several intracellular signal transduction pathways, including Wnt/␤-catenin, PI3K/Akt, Rho GTPase, and NF-B signaling. Recent progress uncovered a novel and critical role for this adhesion molecule in mononuclear phagocyte functions. Ecadherin regulates the maturation and migration of Langerhans cells, and its ligation prevents the induction of a tolerogenic state in bone marrow-derived dendritic cells (DCs). In this respect, the functionality of ␤-catenin could be instrumental in determining the balance between immunogenicity and tolerogenicity of DCs in vitro and in vivo. Fusion of alternatively activated macrophages and osteoclasts is also Ecadherin-dependent. In addition, the Ecadherin ligands CD103 and KLRG1 are expressed on DC-, T-, and NK-cell subsets and contribute to their interaction with E-cadherin-expressing DCs and macrophages. Here we discuss the regulation, function, and implications of Ecadherin expression in these central orchestrators of the immune system. (Blood. 2012;119(7):1623-1633) IntroductionCadherins are transmembrane or membrane-associated glycoproteins that mediate Ca 2ϩ -dependent cell-cell adhesion and have mainly been described for their instrumental role during morphogenesis of a variety of organs. 1 The cadherin superfamily composes classic type I cadherins, closely related type II cadherins, desmosomal cadherins, protocadherins, and several cadherin-related molecules. Cadherin-1 (encoded by Cdh1), also known as CD324, uvomorulin, or E-cadherin, in which the "E" stands for "epithelial," is the founding member of the classic type I cadherin family, which also includes N-cadherin (neural, Cdh2), P-cadherin (placental, Cdh3), Cdh4), and VE-cadherin (vascular endothelial, Cdh5). For several decades, E-cadherin has been known as a major constituent of adherens junctions (AJs), mediating strong homotypic adhesion between neighboring epithelial cells, thereby safeguarding epithelial barrier integrity. 2 The lack of functional tight junction and desmosome formation in the absence of E-cadherin emphasizes its central role in the regulation of epithelial cell-cell contacts. 3 Cell-cell adhesion is mainly executed by the formation of E-cadherin trans-homodimers. Indeed, the E-cadherin molecule contains an ectodomain composed of 5 extracellular cadherin (EC1-5) repeats (550 aa in total), in which EC1 composes the HAV peptide sequence responsible for homophilic interactions, a transmembrane region, and a cytoplasmic tail (150 aa). 2 The latter can be further subdivided into a ␤-catenin binding domain and a membrane proximal cytoplasmic/conserved domain, whose core sequence motif DEEGGGEED is important for p120-catenin binding, resulting in the stabilization of the E-cadherin/catenin complex at the cell surface. 4 E-cadhe...

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Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Cited by 56 publications

References 47 publications

Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction

Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction

β-Catenin–regulated myeloid cell adhesion and migration determine wound healing

Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

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