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Inhibitory actions of the NRG-1/ErbB4 pathway in macrophages during tissue fibrosis in heart, skin and lung

Tijdschriftbijdrage - Tijdschriftartikel

The neuregulin-1 (NRG-1)/ErbB system is an endothelium-controlled paracrine system modulating cardiac performance and adaptation. Recent studies indicate that NRG-1 has anti-fibrotic effects in the left ventricle (LV), which were explained by direct actions on cardiac fibroblasts. However, the NRG-1/ErbB system also regulates the function of macrophages. In this study, we hypothesized that the anti-fibrotic effect of NRG-1 in the heart is at least partially mediated through inhibitory effects on macrophages. We also hypothesized that the anti-fibrotic effect of NRG-1 may be active in other organs, such as skin and lung. First, in a mouse model of angiotensin II (ATII)-induced myocardial hypertrophy and fibrosis, NRG-1 treatment (intraperitoneal; 20µg.kg-1.day-1) significantly attenuated myocardial hypertrophy and fibrosis and improved passive ventricular stiffness (4 weeks). Interestingly, 1 week after exposure to ATII, NRG-1 already attenuated myocardial macrophage infiltration and cytokine expression. Furthermore, mice with myeloid-specific deletion of the ErbB4 gene (ErbB4F/FLysM-Cre+/-) showed an intensified myocardial fibrotic response to ATII. Consistently, NRG-1 activated the ErbB4 receptor in isolated macrophages, inhibited PI3K/Akt and STAT3 signaling pathways and reduced the release of inflammatory cytokines. Further experiments showed that the anti-fibrotic and anti-inflammatory effects of NRG-1 were reproducible in mouse models of bleomycin-induced dermal and pulmonary fibrosis. Overall, this study demonstrates that the anti-fibrotic effect of NRG-1 in the heart is linked to an anti-inflammatory activity NRG-1/ErbB4 signaling in macrophages. Secondly, this study shows that NRG-1 has anti-fibrotic and anti-inflammatory effects in other organs than the heart, such as in skin and lung.
Tijdschrift: American journal of physiology : heart and circulatory physiology
ISSN: 0363-6135
Volume: 313
Pagina's: H934 - H945
Jaar van publicatie:2017
Trefwoorden:A1 Journal article
BOF-keylabel:ja
BOF-publication weight:1
CSS-citation score:2
Authors from:Higher Education
Toegankelijkheid:Open