CCN1: A novel inflammation-regulated biphasic immune cell migration modulator
Institute of Medical Immunology, Charité University Medicine Berlin, 13353, Berlin, Germany. Cellular and Molecular Life Sciences CMLS
(Impact Factor: 5.81).
04/2012; 69(18):3101-13. DOI: 10.1007/s00018-012-0981-x
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.
Available from: Judith de Haan
- "However, CCN1 inhibits the migration of macrophages and lymphocytes in autoimmune myocarditis . 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 . 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. "
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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.
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ABSTRACT: The extracellular matrix (ECM) provides structural support by serving as a scaffold for cells, and as such the ECM maintains normal tissue homeostasis and mediates the repair response following injury. In response to myocardial infarction (MI), ECM expression is generally upregulated in the left ventricle (LV), which regulates LV remodeling by modulating scar formation. The ECM directly affects scar formation by regulating growth factor release and cell adhesion and indirectly affects scar formation by regulating the inflammatory, angiogenic, and fibroblast responses. This review summarizes the current literature on ECM expression patterns and fibroblast mechanisms in the myocardium, focusing on the ECM response to MI. In addition, we discuss future research areas that are needed to better understand the molecular mechanisms of ECM action, both in general and as a means to optimize infarct healing.
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ABSTRACT: The circulatory system is the first hierarchically ordered network to form during the development of vertebrates as it is an indispensable means of adequate oxygen and nutrient delivery to developing organs. During the initial phase of vascular development, endothelial lineage-committed cells differentiate, migrate, and coalesce to form the central large axial vessels and their branches. The subsequent phase of vessel expansion (i.e., angiogenesis) involves a cascade of events including endothelial cell migration, proliferation, formation of an immature capillary structure, recruitment of mural cells and deposition of a basement membrane to yield a functional vasculature. These series of events are tightly regulated by the coordinated expression of several angiogenic, morphogenic and guidance factors. The extracellular matrix (ECM) is synthesized and secreted by embryonic cells at the earliest stages of development and forms a pericellular network of bioactive stimulatory and inhibitory angiogenesis regulatory factors. Here we describe the role of a subset of inducible immediate-early gene-encoded, ECM-associated integrin- and heparin-binding proteins referred to as CCN1 (or Cyr61) and CCN2 (or CTGF) and their function in the development of the vascular system. Gene-targeting experiments in mice have identified CCN1 and CCN2 as critical rate-limiting determinants of endothelial cell differentiation and quiescence, mural cell recruitment and basement membrane formation during embryonic vascular development. Emphasis will be placed on the regulation and function of these molecules and their contextual mode of action during vascular development. Further understanding of the mechanisms of CCN1- and CCN2-mediated blood vessel expansion and remodeling would enhance the prospects that these molecules provide for the development of new treatments for vascular diseases.
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