. . . . . . . . . . . . . . . . . . . . . . . Local production of tenascin-C acts as a trigger for monocyte/macrophage recruitment that provokes cardiac dysfunction Dounia Abbadi 1 , Fanny Laroumanie 1 , Mathilde Bizou 1 , Joffrey Pozzo 1,2 , Danie `le Daviaud 1 , Christine Delage 3 , Denis Calise 3 , Fre ´derique Gaits-Iacovoni 1 , Marianne Dutaur 1 , Florence Tortosa 1 , Edith Renaud-Gabardos 1 , Victorine Douin-Echinard 1 , Anne-Catherine Prats 1 , Jerome Roncalli 1,2 , Angelo Parini 1 , and Nathalie Pizzinat 1 * 1 I2MC, Toulouse University, Inserm, UPS, Toulouse, France; 2 Department of Cardiology, University Hospital of Rangueil, Toulouse, France; and 3 UMS006-Microsurgery Facility, 1, avenue du Professeur Jean Poulhe ´s, Toulouse, France Received 13 February 2017; revised 21 September 2017; editorial decision 12 October 2017; accepted 9 November 2017; online publish-ahead-of-print 10 November 2017 Time for primary review: 47 days 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/mac- rophage (MO/MU) 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/MU 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/MU 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.                                                                                                                                                                                                                     Keywords Tenascin-C • Monocytes • Macrophages • Heart 1. Introduction Heart failure (HF) is a leading cause of mortality worldwide and repre- sents the end-stage of cardiac diseases from different aetiologies. Recently, accumulating evidence has highlighted the causative contribu- tion of immune cells in heart failure. Indeed, both adaptive and innate immune cells seem to play a critical role in exacerbating pathological cardiac remodelling, leading to the development of HF during chronic pressure overload. 1,2 Monocytes/macrophages (MO/MUs) have been described as a major group of leucocytes infiltrating hypertrophic hearts. 2,3 Macrophages are phenotypically plastic cells that are highly influenced by the microenvironment in which they reside. They are gen- erally categorized into M1 or M2 polarization states, achieved, in vitro, by treating macrophages with interferon-c/lipopolysaccharide (IFNc/LPS) * Corresponding author. Tel: þ33 5 31 22 41 20; fax: þ33 5 62 17 25 54, E-mail: nathalie.pizzinat@inserm.fr Published on behalf of the European Society of Cardiology. All rights reserved. V C The Author 2017. For permissions, please email: journals.permissions@oup.com. Cardiovascular Research (2018) 114, 123–137 doi:10.1093/cvr/cvx221 Downloaded from https://academic.oup.com/cardiovascres/article/114/1/123/4616613 by guest on 18 February 2023