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

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          Abstract

          The neuregulin-1 (NRG-1)/receptor tyrosine-protein kinase erbB (ErbB) system is an endothelium-controlled paracrine system modulating cardiac performance and adaptation. Recent studies have indicated that NRG-1 has antifibrotic effects in the left ventricle, 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 antifibrotic effect of NRG-1 in the heart is at least partially mediated through inhibitory effects on macrophages. We also hypothesized that the antifibrotic effect of NRG-1 may be active in other organs, such as the skin and lung. First, in a mouse model of angiotensin II (ANG II)-induced myocardial hypertrophy and fibrosis, NRG-1 treatment (20 µg·kg-1·day-1 ip) significantly attenuated myocardial hypertrophy and fibrosis and improved passive ventricular stiffness (4 wk). Interestingly, 1 wk after exposure to ANG II, 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 ANG II. Consistently, NRG-1 activated the ErbB4 receptor in isolated macrophages, inhibited phosphatidylinositide 3-kinase/Akt and STAT3 signaling pathways, and reduced the release of inflammatory cytokines. Further experiments showed that the antifibrotic 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 antifibrotic effect of NRG-1 in the heart is linked to anti-inflammatory activity NRG-1/ErbB4 signaling in macrophages. Second, this study shows that NRG-1 has antifibrotic and anti-inflammatory effects in organs other than the heart, such as the skin and lung.NEW & NOTEWORTHY Our study contributes to the understanding of the antifibrotic effect of neuregulin-1 during myocardial remodeling. Here, we show that the antifibrotic effect of neuregulin-1 is at least partially mediated through anti-inflammatory activity, linked to receptor tyrosine-protein kinase erbB-4 activation in macrophages. Furthermore, we show that this effect is also present outside the heart.

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          Author and article information

          Journal
          Am. J. Physiol. Heart Circ. Physiol.
          American journal of physiology. Heart and circulatory physiology
          American Physiological Society
          1522-1539
          0363-6135
          Nov 01 2017
          : 313
          : 5
          Affiliations
          [1 ] Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
          [2 ] Center of Medical Genetics, University of Antwerp, Antwerp, Belgium.
          [3 ] Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium.
          [4 ] Department of Cardiology, Middelheim Hospital, Antwerp, Belgium; and.
          [5 ] Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium; vincent.segers@uantwerpen.be.
          [6 ] Department of Cardiology, University Hospital Antwerp, Edegem, Belgium.
          Article
          ajpheart.00206.2017
          10.1152/ajpheart.00206.2017
          28822966
          6d5e6582-9f87-46d4-be73-c3a5e76bc5cd
          History

          receptor tyrosine-protein kinase erbB-4,neuregulin-1,fibrosis,heart failure,macrophages

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