Matricellular signaling molecule CCN1 attenuates experimental autoimmune myocarditis by acting as a novel immune cell migration modulator.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Institute for Medical Immunology, Charite Campus, Berlin, Germany.
Madlen
M
Rother
Stefanie
S
Krohn
Gabriela
G
Kania
Davy
D
Vanhoutte
Andreas
A
Eisenreich
Xiaomin
X
Wang
Dirk
D
Westermann
Kostas
K
Savvatis
Nadine
N
Dannemann
Carsten
C
Skurk
Denise
D
Hilfiker-Kleiner
Toni
T
Cathomen
Henry
H
Fechner
Ursula
U
Rauch
Heinz-Peter
HP
Schultheiss
Stephane
S
Heymans
Urs
U
Eriksson
Carmen
C
Scheibenbogen
Wolfgang
W
Poller
D000328:Adult; D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D032701:Biomimetics; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009205:Myocarditis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D055515:Cysteine-Rich Protein 61; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; C507169:cyclic arginine-glycine-aspartic acid peptide