Local production of tenascin-C acts as a trigger for monocyte/macrophage recruitment that provokes cardiac dysfunction.
Aims
Tenascin-C (TNC) is an endogenous danger signal molecule strongly associated with inflammatory diseases and with poor outcome in patients with cardiomyopathies. Its function within pathological cardiac tissue during pressure overload remains poorly understood.


Methods and results
We showed that TNC accumulates after 1 week of transverse aortic constriction (TAC) in the heart of 12-week-old male mice. By cross bone marrow transplantation experiments, we determined that TNC deposition relied on cardiac cells and not on haematopoietic cells. The expression of TNC induced by TAC, or by administration of a recombinant lentivector coding for TNC, triggered a pro-inflammatory cardiac microenvironment, monocyte/macrophage (MO/MΦ) accumulation, and systolic dysfunction. TNC modified macrophage polarization towards the pro-inflammatory phenotype and stimulated RhoA/Rho-associated protein kinase (ROCK) pathways to promote mesenchymal to amoeboid transition that enhanced macrophage migration into fibrillar collagen matrices. The amplification of inflammation and MO/MΦ recruitment by TNC was abrogated by genetic invalidation of TNC in knockout mice. These mice showed less ventricular remodelling and an improved cardiac function after TAC as compared with wild-type mice.


Conclusions
By promoting a pro-inflammatory microenvironment and macrophage migration, TNC appears to be a key factor to enable the MO/MΦ accumulation within fibrotic hearts leading to cardiac dysfunction. As TNC is highly expressed during inflammation and sparsely during the steady state, its inhibition could be a promising therapeutic strategy to control inflammation and immune cell infiltration in heart disease.
['Abbadi|Dounia|D|', 'Laroumanie|Fanny|F|', 'Bizou|Mathilde|M|', 'Pozzo|Joffrey|J|', 'Daviaud|Danièle|D|', 'Delage|Christine|C|', 'Calise|Denis|D|', 'Gaits-Iacovoni|Fréderique|F|', 'Dutaur|Marianne|M|', 'Tortosa|Florence|F|', 'Renaud-Gabardos|Edith|E|', 'Douin-Echinard|Victorine|V|', 'Prats|Anne-Catherine|AC|', 'Roncalli|Jerome|J|', 'Parini|Angelo|A|', 'Pizzinat|Nathalie|N|']
D000818:Animals D002465:Cell Movement D060833:Cellular Microenvironment D018925:Chemokines D004195:Disease Models, Animal D005355:Fibrosis D017379:Hypertrophy, Left Ventricular D018836:Inflammation Mediators D008264:Macrophages D008297:Male D008810:Mice, Inbred C57BL D018345:Mice, Knockout D009000:Monocytes D009206:Myocardium D010641:Phenotype D015398:Signal Transduction D019063:Tenascin D018487:Ventricular Dysfunction, Left D016277:Ventricular Function, Left D020257:Ventricular Remodeling D020741:rho GTP-Binding Proteins D054460:rho-Associated Kinases D020742:rhoA GTP-Binding Protein
Tenascin-C Monocytes Macrophages Heart