Matricellular Signaling Molecule CCN1 Attenuates Experimental Autoimmune Myocarditis by Acting as a Novel Immune Cell Migration Modulator

• Published in: Circulation (New York, N.Y.) N.Y.), 2010-12, Vol.122 (25), p.2688-2698
• Main Authors: ROTHER, Madlen, KROHN, Stefanie, HILFIKER-KLEINER, Denise, CATHOMEN, Toni, FECHNER, Henry, RAUCH, Ursula, SCHULTHEISS, Heinz-Peter, HEYMANS, Stephane, ERIKSSON, Urs, SCHEIBENBOGEN, Carmen, POLLER, Wolfgang, KANIA, Gabriela, VANHOUTTE, Davy, EISENREICH, Andreas, XIAOMIN WANG, WESTERMANN, Dirk, SAVVATIS, Kostas, DANNEMANN, Nadine, SKURK, Carsten
• Format: Article
• Language: English
• Subjects: Adult; Animal models; Animals; Autoimmune Diseases - metabolism; Autoimmune Diseases - pathology; Autoimmune Diseases - prevention & control; Biological and medical sciences; Biomimetics; Blood and lymphatic vessels; Blood vessels and receptors; Cancer; Cardiology. Vascular system; cardiomyocytes; Cardiomyopathy; Cell migration; Cell Movement - drug effects; Cell Movement - physiology; Cells, Cultured; Chemokines; Chemotactic factors; Chemotactic response; Chemotaxis; Cysteine-Rich Protein 61 - genetics; Cysteine-Rich Protein 61 - metabolism; Cysteine-Rich Protein 61 - pharmacology; Cytokines; Data processing; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Evolution; Expression vectors; Female; Fundamental and applied biological sciences. Psychology; Gene transfer; Gene Transfer Techniques; Heart diseases; Hemagglutinins; Humans; Immunosuppressive agents; Inflammation; Injuries; Ischemia; Leukocyte migration; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Liver - cytology; Liver - drug effects; Lymphocytes; Macrophages; Male; Medical sciences; Mice; Mice, Inbred BALB C; Middle Aged; Monocytes; Monocytes - cytology; Monocytes - drug effects; Myocarditis; Myocarditis - metabolism; Myocarditis - pathology; Myocarditis - prevention & control; Peptides, Cyclic - pharmacology; Recombinant Proteins - pharmacology; SDF-1 protein; Spleen; Spleen - cytology; Spleen - drug effects; Vertebrates: cardiovascular system; Wounds
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.110.945261

CCN1 is an evolutionary ancient matricellular protein that modulates biological processes associated with tissue repair. Induction at sites of injury was observed in conditions ranging from skin wounds to cardiac diseases, including ischemic and inflammatory cardiomyopathy. Here, we provide evidence of a novel function of CCN1 as a modulator of immune cell migration. to understand the role of CCN1 in cardiomyopathies and to evaluate its therapeutic potential, we overexpressed CCN1 using an adenoviral hepatotropic vector in murine experimental autoimmune myocarditis, a model of human inflammatory cardiomyopathy. CCN1 gene transfer significantly reduced cardiac disease score and immune cell infiltration. In vivo tracking of hemagglutinin epitope-tagged CCN1 revealed binding to spleen macrophages but not to cardiomyocytes. Unexpectedly, CCN1 therapy left cardiac chemokine and cytokine expression unchanged but instead strongly inhibited the migration of spleen macrophages and lymphocytes, as evidenced by ex vivo transwell assays. In accordance with the ex vivo data, in vitro preincubation with CCN1 diminished transwell migration of human monocytes and abrogated their chemotactic response to monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and stromal cell-derived factor-1α. Further mechanistic studies showed that CCN1-driven modulation of immune cell migration is mimicked in part by cyclic RGD peptides currently in clinical evaluation for cancer therapy. our proof-of-concept study suggests investigation of CCN1 as a novel, endogenous "parent compound" for chemotaxis modulation and of cyclic RGD peptides as a class of partially CCN1-mimetic drugs with immediate potential for clinical evaluation in cardiac diseases associated with chronic pathogenic inflammation.