CCN1: A novel inflammation-regulated biphasic immune cell migration modulator

ArticleinCellular and Molecular Life Sciences CMLS 69(18):3101-13 · April 2012with46 Reads
DOI: 10.1007/s00018-012-0981-x · Source: PubMed
Abstract
In this study, we performed a comprehensive analysis of the effect of CCN1 on the migration of human immune cells. The molecule CCN1, produced by fibroblasts and endothelial cells, is considered as an important matrix protein promoting tissue repair and immune cell adhesion by binding various integrins. We recently reported that CCN1 therapy is able to suppress acute inflammation in vivo. Here, we show that CCN1 binds to various immune cells including T cells, B cells, NK cells, and monocytes. The addition of CCN1 in vitro enhances both actin polymerization and transwell migration. Prolonged incubation with CCN1, however, results in the inhibition of migration of immune cells by a mechanism that involves downregulation of PI3Kγ, p38, and Akt activation. Furthermore, we observed that immune cells themselves produce constitutively CCN1 and secretion is induced by pro-inflammatory stimuli. In line with this finding, patients suffering from acute inflammation had enhanced serum levels of CCN1. These findings extend the classical concept of CCN1 as a locally produced cell matrix adhesion molecule and suggest that CCN1 plays an important role in regulating immune cell trafficking by attracting and locally immobilizing immune cells.
    • "The condition of HCC inflammatory microenvironment is now recognized as a hallmark feature of tumor development and metastasis [8]. The functions of CCN proteins are involved in the regulations of inflammatory microenvironment [15, 96, 97]. In particular, CCNs expression is regulated by cytokines and immune cells, and that, reciprocally, CCNs may regulate cytokines, chemokines expression and immune cell functions. "
    [Show abstract] [Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) results from an underlying chronic liver inflammatory disease, such as chronic hepatitis B or C virus infections, and the general prognosis of patients with HCC still remains extremely dismal because of the high frequency of HCC metastases. Throughout the process of tumor metastasis, tumor cells constantly communicate with the surrounding microenvironment and improve their malignant phenotype. Therefore, there is a strong rationale for targeting the tumor microenvironment as primary treatment of HCC therapies. Recently, CCN family proteins have emerged as localized multitasking signal integrators in the inflammatory microenvironment. In this review, we summarize the current knowledge of CCN family proteins in inflammation and the tumor. We also propose that the CCN family proteins may play a central role in signaling the tumor microenvironment and regulating the metastasis of HCC.
    Full-text · Article · Oct 2015
    • "However, CCN1 inhibits the migration of macrophages and lymphocytes in autoimmune myocarditis [150]. To explain the paradoxical role of CCN1, Löbel and colleagues showed a diphasic immune modulator response for CCN1; initial stimulation with CCN1 attracts and activates leukocytes; however, prolonged CCN1 stimulation and enhanced secretion of CCN1 by leukocytes immobilize systemic leukocytes [151]. It can be speculated that CCN1 may function as a danger signal after MI by attracting and activating leukocytes, however, in vivo studies are necessary to state this. "
    [Show abstract] [Hide abstract] ABSTRACT: During myocardial infarction, sterile inflammation occurs. The danger model is a solid theoretic framework that explains this inflammation as danger associated molecular patterns activate the immune system. The innate immune system can sense danger signals through different pathogen recognition receptors (PRR) such as toll-like receptors, nod-like receptors and receptors for advanced glycation endproducts. Activation of a PRR results in the production of cytokines and the recruitment of leukocytes to the site of injury. Due to tissue damage and necrosis of cardiac cells, danger signals such as extracellular matrix (ECM) breakdown products, mitochondrial DNA, heat shock proteins and high mobility box 1 are released. Matricellular proteins are non-structural proteins expressed in the ECM and are upregulated upon injury. Some members of the matricellular protein family (like tenascin-C, osteopontin, CCN1 and the galectins) have been implicated in the inflammatory and reparative responses following myocardial infarction and may function as danger signals. In a clinical setting, danger signals can function as prognostic and/or diagnostic biomarkers and for drug targeting. In this review we will provide an overview of the established knowledge on the role of danger signals in myocardial infarction and we will discuss areas of interest for future research.
    Full-text · Article · Nov 2013
    • "In conclusion, this study points to DNA topo I and Clks to be -at least in parts -involved in the differential isoform expression of Cyr61 and Itg α v by regulation of post-transcriptional splicing in resting as well as in TNF-α-induced human microvascular endothelial cells. Both proteins were known to play an essential role in vascular diseases as well as in endothelial regeneration [4,7,31,32]. Our findings indicate that post-transcriptional modulation of the differential isoform expression of Cyr61 may be involved in the regulation of important regenerative endothelial functions, such as cell proliferation and angiogenesis. "
    [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND: Endothelial cells regulate angiogenesis and vessel wall homeostasis via bioactive factors, such as cysteine-rich 61 (Cyr61) and Integrin-αv (Itgαv). Pre-mRNA splicing leads to the expression of two Cyr61 mRNA splice variants (Cyr61_IS, Cyr61_IR) and three Itgαv isoforms (Itgαv_1, 2, 3). Splicing is important for the functional multiplicity and is regulated via the serine/arginine-rich (SR) protein kinases, Cdc2-like kinases (Clk) and DNA topoisomerase I (DNA topo I). Here, we study the impact of these SR protein kinases on the Cyr61 and Itgαv isoform expression as well as on the endothelial cell proliferation and pro-angiogenic properties of human microvascular endothelial cells (HMEC-1). METHODS: We assessed the expression of Cyr61 and Itgαv isoforms via RT-PCR and Western blotting. Cellular functions were determined by adequate assays (MTT proliferation assay, in vitro angiogenesis assay). RESULTS: We found Clks as well as DNA topo I to modulate the differential isoform expression of Cyr61 and Itgαv, the protein expression and secretion in resting as well as in TNF-α-stimulated HMEC-1. Moreover, these processes affected the endothelial cell proliferation and pro-angiogenic tube formation by HMEC-1. Finally, treatment of cells with recombinant Cyr61_IS or siRNA-mediated silencing of Cyr61_IS and Cyr61_IR also modulated these functions. CONCLUSIONS: This study indicates DNA topo I and Clks to regulate the differential isoform expression Cyr61 and Itgαv and to affect regenerative endothelial functions under normal and pro-inflammatory conditions.
    Full-text · Article · Jul 2013
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Comments

June 9, 2016
Charité Universitätsmedizin Berlin
Thank you for this kind comment. In my opinion, Lester Lau has an neutralizing antibody against CCN1 activity. Best wishes.
June 7, 2016
Università degli Studi di Sassari
Thank you, Very interesting article. I'm wondering why nobody investigated on CCN1 and different autoimmune diseases. Multiple sclerosis would be a perfect setting to investigate. Moreover no monoclonal CCN1 neutralizing antibodies are available yet?

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