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  • 1
    Online Resource
    Online Resource
    Kindlin‐2 interacts with endothelial adherens junctions to support vascular barrier integrity
    Wiley ; 2017
    In:  The Journal of Physiology Vol. 595, No. 20 ( 2017-10-15), p. 6443-6462
    Details
    In: The Journal of Physiology, Wiley, Vol. 595, No. 20 ( 2017-10-15), p. 6443-6462
    Abstract: A reduction in Kindlin‐2 levels in endothelial cells compromises vascular barrier function. Kindlin‐2 is a previously unrecognized component of endothelial adherens junctions. By interacting directly and simultaneously with β‐ or γ‐catenin and cortical actin filaments, Kindlin‐2 stabilizes adherens junctions. The Kindlin‐2 binding sites for β‐ and γ‐catenin reside within its F1 and F3 subdomains. Although Kindlin‐2 does not associate directly with tight junctions, its downregulation also destabilizes these junctions. Thus, impairment of both adherens and tight junctions may contribute to enhanced leakiness of vasculature in Kindlin‐2 +/− mice.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    URL: Article
    DOI: 10.1113/tjp.2017.595.issue-20
    DOI: 10.1113/JP274380
    RVK:
    WA 15000
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 1475290-6
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    The P387 thrombospondin‐4 variant promotes accumulation of macrophages in atherosclerotic lesions
    Wiley ; 2020
    In:  The FASEB Journal Vol. 34, No. 9 ( 2020-09), p. 11529-11545
    Details
    In: The FASEB Journal, Wiley, Vol. 34, No. 9 ( 2020-09), p. 11529-11545
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v34.9
    DOI: 10.1096/fj.201901434RRRR
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    miR‐467 regulates inflammation and blood insulin and glucose
    Wiley ; 2021
    In:  Journal of Cellular and Molecular Medicine Vol. 25, No. 5 ( 2021-03), p. 2549-2562
    Details
    In: Journal of Cellular and Molecular Medicine, Wiley, Vol. 25, No. 5 ( 2021-03), p. 2549-2562
    Abstract: Obesity is associated with inflammation and insulin resistance (IR), but the regulation of insulin sensitivity (IS) and connections between IS and inflammation remain unclear. We investigated the role of miR‐467a‐5p, a miRNA induced by hyperglycaemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR‐467a‐5p is induced by hyperglycaemia and inhibits the production of thrombospondin‐1 (TSP‐1), a protein implicated in regulating inflammation. To investigate the role of miR‐467 in blood glucose handling and tissue inflammation, WT C57BL/6 mice were fed chow or Western diet from 5 to 32 weeks of age and injected weekly with miR‐467a‐5p antagonist. Inhibiting miR‐467a‐5p resulted in 47% increase in macrophage infiltration and increased Il6 levels in adipose tissue, higher plasma insulin levels (98 ng/mL vs 63 ng/mL), and 17% decrease in glucose clearance without increase in weight or HDL/LDL. The antagonist effect was lost in mice on Western diet. Mice lacking TSP‐1 lost some but not all of the miR‐467 effects, suggesting Thbs1 (and other unknown transcripts) are targeted by miR‐467 to regulate inflammation. miR‐467a‐5p provides a physiological feedback when blood glucose is elevated to avoid inflammation and increased blood glucose and insulin levels, which may prevent IR.
    Type of Medium: Online Resource
    ISSN: 1582-1838 , 1582-4934
    URL: Issue
    URL: Article
    DOI: 10.1111/jcmm.v25.5
    DOI: 10.1111/jcmm.16224
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2076114-4
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  • 4
    Online Resource
    Online Resource
    Thrombospondin‐4 mediates hyperglycemia‐ and TGF ‐beta‐induced inflammation in breast cancer
    Wiley ; 2021
    In:  International Journal of Cancer Vol. 148, No. 8 ( 2021-04-15), p. 2010-2022
    Details
    In: International Journal of Cancer, Wiley, Vol. 148, No. 8 ( 2021-04-15), p. 2010-2022
    Abstract: What's new? Thrombospondin‐4 (TSP‐4), a secreted extracellular protein, is upregulated in several cancers, including breast cancer. TSP‐4 also is associated with diabetes, in which hyperglycemia influences inflammation and potentially increases cancer risk. This study shows that TSP‐4 is linked to inflammation and infiltration of macrophages in samples from breast cancer patients and in mouse models of breast cancer. Moreover, in breast tumors from hyperglycemic animals, TSP‐4 mediated the effects of hyperglycemia and TGF‐beta on cancer growth and inflammation. The findings highlight the influence of TSP‐4 on cancer inflammation and growth and warrant further study of TSP‐4 as a possible therapeutic target.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v148.8
    DOI: 10.1002/ijc.33439
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 5
    Online Resource
    Online Resource
    Kindlin-3 deficiency leads to impaired erythropoiesis and erythrocyte cytoskeleton
    American Society of Hematology ; 2023
    In:  Blood Advances Vol. 7, No. 9 ( 2023-05-09), p. 1739-1753
    Details
    In: Blood Advances, American Society of Hematology, Vol. 7, No. 9 ( 2023-05-09), p. 1739-1753
    Abstract: Kindlin-3 (K3) is critical for the activation of integrin adhesion receptors in hematopoietic cells. In humans and mice, K3 deficiency is associated with impaired immunity and bone development, bleeding, and aberrant erythrocyte shape. To delineate how K3 deficiency (K3KO) contributes to anemia and misshaped erythrocytes, mice deficient in erythroid (K3KO∖EpoR-cre) or myeloid cell K3 (K3KO∖Lyz2cre), knockin mice expressing mutant K3 (Q597W598 to AA) with reduced integrin-activation function (K3KI), and control wild-type (WT) K3 mice were studied. Both K3-deficient strains and K3KI mice showed anemia at baseline, reduced response to erythropoietin stimulation, and compromised recovery after phenylhydrazine (PHZ)-induced hemolytic anemia as compared with K3WT. Erythroid K3KO and K3 (Q597W598 to AA) showed arrested erythroid differentiation at proerythroblast stage, whereas macrophage K3KO showed decreased erythroblast numbers at all developmental stages of terminal erythroid differentiation because of reduced erythroblastic island (EBI) formation attributable to decreased expression and activation of erythroblast integrin α4β1 and macrophage αVβ3. Peripheral blood smears of K3KO∖EpoR-cre mice, but not of the other mouse strains, showed numerous aberrant tear drop–shaped erythrocytes. K3 deficiency in these erythrocytes led to disorganized actin cytoskeleton, reduced deformability, and increased osmotic fragility. Mechanistically, K3 directly interacted with F-actin through an actin-binding site K3-LK48. Taken together, these findings document that erythroid and macrophage K3 are critical contributors to erythropoiesis in an integrin-dependent manner, whereas F-actin binding to K3 maintains the membrane cytoskeletal integrity and erythrocyte biconcave shape. The dual function of K3 in erythrocytes and in EBIs establish an important functional role for K3 in normal erythroid function.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2022008498
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
    detail.hit.zdb_id: 2876449-3
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  • 6
    Online Resource
    Online Resource
    Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 6 ( 2021-03-16), p. 1346-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 6 ( 2021-03-16), p. 1346-
    Abstract: The tumor microenvironment contains the parenchyma, blood vessels, and infiltrating immune cells, including tumor-associated macrophages (TAMs). TAMs affect the developing tumor and drive cancer inflammation. We used mouse models of hyperglycemia and cancer and specimens from hyperglycemic breast cancer (BC) patients to demonstrate that miR-467 mediates the effects of high blood glucose on cancer inflammation and growth. Hyperglycemic patients have a higher risk of developing breast cancer. We have identified a novel miRNA-dependent pathway activated by hyperglycemia that promotes BC angiogenesis and inflammation supporting BC growth. miR-467 is upregulated in endothelial cells (EC), macrophages, BC cells, and in BC tumors. A target of miR-467, thrombospondin-1 (TSP-1), inhibits angiogenesis and promotes resolution of inflammation. Systemic injections of a miR-467 antagonist in mouse models of hyperglycemia resulted in decreased BC growth (p 〈 0.001). Tumors from hyperglycemic mice had a two-fold increase in macrophage accumulation compared to normoglycemic controls (p 〈 0.001), and TAM infiltration was prevented by the miR-467 antagonist (p 〈 0.001). BC specimens from hyperglycemic patients had increased miR-467 levels, increased angiogenesis, decreased levels of TSP-1, and increased TAM infiltration in malignant breast tissue in hyperglycemic vs. normoglycemic patients (2.17-fold, p = 0.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold increase, p = 0.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (p 〈 0.001) and increased 56-fold in adjacent normal tissue (p = 0.008). Our results suggest that miR-467 accelerates tumor growth by inducing angiogenesis and promoting the recruitment of TAMs to drive hyperglycemia-induced cancer inflammation.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13061346
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 7
    Online Resource
    Online Resource
    αMβ2 Is Antiatherogenic in Female but Not Male Mice
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 7 ( 2018-04-01), p. 2426-2438
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 7 ( 2018-04-01), p. 2426-2438
    Abstract: Atherosclerosis is a complex inflammatory process characterized by monocyte recruitment into the arterial wall, their differentiation into macrophages, and lipid accumulation. Because integrin αMβ2 (CD11b/CD18) mediates multiple diverse functions of leukocytes, we examined its role in atherogenesis. αM−/−/ApoE−/− and ApoE−/− mice were fed a control or high fat diet for 3 or 16 wk to induce atherogenesis. Unexpectedly, αM deficiency accelerated development of atherosclerosis in female but not in male mice. The size of aortic root lesions was 3–4.5-fold larger in female αM−/−/ApoE−/− than in ApoE−/− mice. Monocyte and macrophage content within the lesions was increased 2.5-fold in female αM−/−/ApoE−/− mice due to enhanced proliferation. αMβ2 elimination promoted gender-dependent foam cell formation due to enhanced uptake of cholesterol by αM−/−/ApoE−/− macrophages. This difference was attributed to enhanced expression of lipid uptake receptors, CD36 and scavenger receptor A1 (SR-A1), in female mice. Macrophages from female αM−/−/ApoE−/− mice showed dramatically reduced expression of FoxM1 transcription factor and estrogen receptors (ER) α and β. As their antagonists inhibited the effect of 17β-estradiol (E2), E2 decreased CD36, SR-A1, and foam cell formation in ApoE−/− macrophages in an ERα- and ERβ-dependent manner. However, female αM−/−/ApoE−/− macrophages failed to respond to E2 and maintained elevated CD36, SR-A1, and lipid accumulation. FoxM1 inhibition in ApoE−/− macrophages reduced ERs and enhanced CD36 and SR-A1 expression, whereas FoxM1 overexpression in αM−/−/ApoE−/− macrophages reversed their proatherogenic phenotype. We demonstrate a new, surprising atheroprotective role of αMβ2 in female ApoE−/− mice. αMβ2 maintains ER expression in macrophages and E2-dependent inhibition of foam cell formation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1700313
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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  • 8
    Online Resource
    Online Resource
    Integrin αXβ2 Is a Leukocyte Receptor for Candida albicans and Is Essential for Protection against Fungal Infections
    The American Association of Immunologists ; 2012
    In:  The Journal of Immunology Vol. 189, No. 5 ( 2012-09-01), p. 2468-2477
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 189, No. 5 ( 2012-09-01), p. 2468-2477
    Abstract: The opportunistic fungus Candida albicans is one of the leading causes of infections in immunocompromised patients, and innate immunity provides a principal mechanism for protection from the pathogen. In the present work, the role of integrin αXβ2 in the pathogenesis of fungal infection was assessed. Both purified αXβ2 and αXβ2-expressing human epithelial kidney 293 cells recognized and bound to the fungal hyphae of SC5314 strain of C. albicans but not to the yeast form or to hyphae of a strain deficient in the fungal mannoprotein, Pra1. The binding of the integrin to the fungus was inhibited by β-glucans but not by mannans, implicating a lectin-like activity in recognition but distinct in specificity from that of αMβ2. Mice deficient in αXβ2 were more prone to systemic infection with the LD50 fungal inoculum decreasing 3-fold in αXβ2-deficient mice compared with wild-type mice. After challenging i.v. with 1.5 × 104 cell/g, 60% of control C57BL/6 mice died within 14 d compared with 100% mortality of αXβ2-deficient mice within 9 d. Organs taken from αXβ2-deficient mice 16 h postinfection revealed a 10-fold increase in fungal invasion into the brain and a 2-fold increase into the liver. These data indicate that αXβ2 is important for protection against systemic C. albicans infections and macrophage subsets in the liver, Kupffer cells, and in the brain, microglial cells use αXβ2 to control fungal invasion.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1200524
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2012
    detail.hit.zdb_id: 1475085-5
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  • 9
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    Online Resource
    Effects of thrombospondin-4 on pro-inflammatory phenotype differentiation and apoptosis in macrophages
    Springer Science and Business Media LLC ; 2020
    In:  Cell Death & Disease Vol. 11, No. 1 ( 2020-01-23)
    Details
    In: Cell Death & Disease, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-01-23)
    Abstract: Thrombospondin-4 (TSP-4) attracted renewed attention recently as a result of assignment of new functions to this matricellular protein in cardiovascular, muscular, and nervous systems. We have previously reported that TSP-4 promotes local vascular inflammation in a mouse atherosclerosis model. A common variant of TSP-4, P387-TSP-4, was associated with increased cardiovascular disease risk in human population studies. In a mouse atherosclerosis model, TSP-4 had profound effect on accumulation of macrophages in lesions, which prompted us to examine its effects on macrophages in more detail. We examined the effects of A387-TSP-4 and P387-TSP-4 on mouse macrophages in cell culture and in vivo in the model of LPS-induced peritonitis. In tissues and in cell culture, TSP-4 expression was associated with inflammation: TSP-4 expression was upregulated in peritoneal tissues in LPS-induced peritonitis, and pro-inflammatory signals, INFγ, GM-CSF, and LPS, induced TSP-4 expression in macrophages in vivo and in cell culture. Deficiency in TSP-4 in macrophages from Thbs4 − /− mice reduced the expression of pro-inflammatory macrophage markers, suggesting that TSP-4 facilitates macrophage differentiation into a pro-inflammatory phenotype. Expression of TSP-4, especially more active P387-TSP-4, was associated with higher cellular apoptosis. Cultured macrophages displayed increased adhesion to TSP-4 and reduced migration in presence of TSP-4, and these responses were further increased with P387 variant. We concluded that TSP-4 expression in macrophages increases their accumulation in tissues during the acute inflammatory process and supports macrophage differentiation into a pro-inflammatory phenotype. In a model of acute inflammation, TSP-4 supports pro-inflammatory macrophage apoptosis, a response that is closely related to their pro-inflammatory activity and release of pro-inflammatory signals. P387-TSP-4 was found to be the more active form of TSP-4 in all examined functions.
    Type of Medium: Online Resource
    ISSN: 2041-4889
    URL: Article
    DOI: 10.1038/s41419-020-2237-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2541626-1
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