S100A10 regulates plasminogen-dependent macrophage invasion

Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada.
Blood (Impact Factor: 10.45). 08/2010; 116(7):1136-46. DOI: 10.1182/blood-2010-01-264754
Source: PubMed


The plasminogen activation system plays an integral role in the migration of macrophages in response to an inflammatory stimulus, and the binding of plasminogen to its cell-surface receptor initiates this process. Although previous studies from our laboratory have shown the importance of the plasminogen receptor S100A10 in cancer cell plasmin production, the potential role of this protein in macrophage migration has not been investigated. Using thioglycollate to induce a peritoneal inflammatory response, we demonstrate, for the first time, that compared with wild-type (WT) mice, macrophage migration across the peritoneal membrane into the peritoneal cavity in S100A10-deficient (S100A10(-/-)) mice was decreased by up to 53% at 24, 48, and 72 hours. Furthermore, the number of S100A10-deficient macrophages that infiltrated Matrigel plugs was reduced by 8-fold compared with their WT counterpart in vivo. Compared with WT macrophages, macrophages from S100A10(-/-) mice demonstrated a 50% reduction in plasmin-dependent invasion across a Matrigel barrier and a 45% reduction in plasmin generation in vitro. This loss in plasmin-dependent invasion was in part the result of a decreased generation of plasmin and a decreased activation of pro-MMP-9 by S100A10-deficient macrophages. This study establishes a direct involvement of S100A10 in macrophage recruitment in response to inflammatory stimuli.

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    • "Given the detailed knowledge of the binding interactions between the N-terminus of AnxA2 and S100A10, various groups have reported the use of peptides based upon this N-terminus to perform competition experiments with the aim of disrupting the endogenous complex of the two proteins and understanding its functions. An isolated acetylated synthetic peptide comprising residues 1–14 of AnxA2 can disrupt a preformed complex between S100A10 and a labelled annexin 1–14 peptide (O'Connell et al., 2010). Furthermore, the same peptide also disrupts a preformed full-length (S100A10-AnxA2)2 complex (Konig et al., 1998). "
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    ABSTRACT: Annexin A2 (AnxA2) was originally identified as a substrate of the pp60v-src oncoprotein in transformed chicken embryonic fibroblasts (Cooper et al., 1982; Erikson et al., 1984; Gerke et al., 1984). It is an abundant protein that associates with biological membranes as well as the actin cytoskeleton (Harder et al., 1994; Thiel et al., 1992), and has been implicated in intracellular vesicle fusion, the organisation of membrane domains, lipid rafts and membrane-cytoskeleton contacts (Gerke et al., 2005). In addition to an intracellular role, AnxA2 has been reported to participate in processes localised to the cell surface including extracellular protease regulation and cell cell interactions (Bharadwaj et al., 2013; Luo et al., 2013). There are many reports showing that AnxA2 is differentially expressed between normal and malignant tissue and potentially involved in tumour progression. An important aspect of AnxA2 function relates to its interaction with small Ca(2+) dependent adaptor proteins called S100 proteins, which is the topic of this review. The interaction between AnxA2 and S100A10 has been very well characterised historically; more recently other S100 proteins have been shown to interact with AnxA2 as well. The biochemical evidence for the occurrence of these protein interactions will be discussed, as well as their function. Recent studies aiming to generate inhibitors of S100 protein interactions will be described and the potential of these inhibitors to further our understanding of AnxA2 S100 protein interactions will be discussed.
    British Journal of Pharmacology 10/2014; 172(7). DOI:10.1111/bph.12978 · 4.84 Impact Factor
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    • "In mice, S100A4 -/ -animals showed reduced joint inflammation , impaired bone resorption and regulation of osteoclast, increased cartilage and bone destruction, and decreased expression of MMPs (Bian, 2011; Erlandsson et al., 2013). S100A10 expression decreased the production of TNFa, IL- 1b, and IL-10 in chondrocytes (O'Connell et al., 2010; Song et al., 2012). The S100A11 induces chondrocyte hypertrophy and matrix catabolism (Yammani, 2012). "
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    ABSTRACT: We applied global gene expression arrays, quantitative real-time PCR, immunostaining, and functional assays to untangle the role of High Mobility Groups proteins (HMGs) in human Osteoarthritis (OA)-affected cartilage. Bioinformatics analysis showed increased mRNA expression of Damage-Associated Molecular Pattern (DAMPS): HMGA, HMGB, HMGN, SRY, LEF1, HMGB1, MMPs, and HMG/RAGE-interacting molecules (spondins and S100A4, S100A10, and S100A11) in human OA-affected cartilage as compared with normal cartilage. HMGB2 was down-regulated in human OA-affected cartilage. Immunohistological staining identified HMGB1 in chondrocytes in the superficial cartilage. Cells of the deep cartilage and subchondral bone showed increased expression of HMGB1 in OA-affected cartilage. HMGB1 was expressed in the nucleus, cytosol, and extracellular milieu of chondrocytes in cartilage. Furthermore, HMGB1 was spontaneously released from human OA-affected cartilage in ex vivo conditions. The effects of recombinant HMGB1 was tested on human cartilage and chondrocytes in vitro. HMGB1 stimulated mRNA of 2 NFκB gene enhancers (NFκB1 and NFκB2), 16 CC and CXC chemokines (IL-8, CCL2, CCL20, CCL3, CCL3L1, CCL3L3, CCL4, CCL4L1, CCL4L2, CCL5, CCL8, CXCL1, CXCL10, CXCL2, CXCL3, and CXCL6) by ≥10-fold. Furthermore, HMGB1 and IL-1β and/or tumor necrosis factor α (but not HMGI/Y) also significantly induced inducible nitric oxide synthase, NO, and interleukin (IL)-8 production in human cartilage and chondrocytes. The recombinant HMGB1 utilized in this study shows properties that are similar to disulfide-HMGB1. The differential, stage and/or tissue-specific expression of HMGB1, HMGB2, and S100A in cartilage was associated with regions of pathology and/or cartilage homeostasis in human OA-affected cartilage. Noteworthy similarities in the expression of mouse and human HMGB1 and HMGB2 were conserved in normal and arthritis-affected cartilage. The multifunctional forms of HMGB1 and S100A could perpetuate damage-induced cartilage inflammation in late-stage OA-affected joints similar to sterile inflammation. The paracrine effects of HMGB1 can induce chemokines and NO that are perceived to change cartilage homeostasis in human OA-affected cartilage.
    DNA and Cell Biology 06/2014; 33(8). DOI:10.1089/dna.2013.2198 · 2.06 Impact Factor
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    • "The impact of inflammation-immunity state on pathology outcome has been demonstrated by several previous experimental and clinical studies, both as a strong proatherogenic determinant of plaque initiation as well as of its progression and evolution (Lamon and Hajjar, 2008; Merched et al., 2008). By the mathematical model, identified local artery-specific factors, relevantly associated to lesion initiation and growth, are those mainly involved in macrophage/phagocytosis function and immunity-inflammatory pathways (CATA, CATD, S100-A10, FABPH, BGH3) (Haidar et al., 2006; Nacu et al., 2008; O'Connell et al., 2010; Lee et al., 2013). These proteins may be viewed as mediators and possible markers of a local inflammation scenario with pro-and anti-inflammatory elements playing a role in both initiation and early growth of high cholesterol diet-induced coronary atherosclerotic lesions. "
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    ABSTRACT: Purpose: The multifactorial pathogenesis of coronary atherosclerotic lesion formation has been investigated in a swine model of high cholesterol diet induced atherogenesis and data processed by a systems approach. Methods: Farm pigs were fed on standard or high cholesterol diet of 8 and 16 weeks duration. Plasma assessment of total cholesterol, HDL, LDL, and ELISA of some cytokines and ICAM-1 were performed on baseline and end-diet samples. Segments of the right coronary artery were incubated for 24 h in serum-free medium to collect secreted proteins and their expression analyzed by mass spectrometry. Data of plasma and tissue factors were processed by a statistical systems inference approach: both histologic parameters of coronary intimal thickness (IT) and of lesion area (LA) were chosen as dependent variables (coronary atherosclerotic burden). Results: Relations among plasma adhesion molecules, cytokines, lipoproteins, tissue proteins and histology indexes were integrated in a model regression scheme. Bayesian model averaging (BMA) variable selection was chosen as a method to identify relevant factors associated to atherosclerotic burden: TNFα was identified as an associated plasma marker, oxLDL and HDL as relevant lipoproteins; macrophage function related antioxidant Catalase enzyme, lysosome associated Cathepsin D, S100-A10, and Transforming growth factor-beta-induced protein ig-h3 were identified and selected as associated to atherogenesis outcome. Conclusions: The results of this systems approach are consistent with the hypothesis that, in high cholesterol diet-induced experimental atherogenesis, the interaction between plasma cytokines, lipoproteins and artery-specific proteins, influences lesion initiation and growth. In particular, some macrophage function related proteins are found significantly and positively associated to atherosclerotic burden, suggesting a novel molecular framework into the atherogenesis-inflammatory disorder.
    Frontiers in Genetics 04/2014; 5:70. DOI:10.3389/fgene.2014.00070
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