The protective role of NRG-1/ErbB signaling during tissue fibrosis
25 October 2017
UAntwerpen, Stadscampus, Hof van Liere, F. de Tassis Hall - Prinsstraat 13 - 2000 Antwerpen (route: UAntwerpen, Stadscampus
3:30 PM - 5:30 PM
Gilles De Keulenaer
PhD defence Zarha Vermeulen - Department of Pharmaceutical Sciences
Introduction: The NRG-1/ErbB system has been well studied for its indispensable role in the development and protection of the heart. Its cardioprotective functions have generally been explained by the activation of ErbB2 and ErbB4 receptors in cardiomyocytes. However, recent studies indicate that NRG-1 also has anti-fibrotic effects in the LV, implicating effects of NRG-1 on non-myocytes, including fibroblasts and macrophages. we investigated the role of NRG-1 in myocardial fibrosis by activating (rhNRG-1 administration) or inhibiting (transgenic mice) the NRG-1/ErbB signaling pathway. Secondly, we investigated if these anti-fibrotic effects are reproducible in other fibrotic disorders, including dermal and pulmonary fibrosis. Finally, we studied the effect of ErbB4 gene deletion in fibroblasts and macrophages during tissue fibrosis.
Methods and Results: We demonstrated the anti-fibrotic effects of NRG-1 in ATII-induced myocardial fibrosis and extended these findings by showing that NRG-1 attenuates dermal and pulmonary fibrosis. These anti-fibrotic properties of NRG-1 were first explained by direct inhibitory actions on fibroblasts via ErbB4. While investigating the underlying mechanisms using microarray analysis, we unexpectedly discovered that NRG-1 also exerts anti-inflammatory effects. Subsequently, we found that NRG-1 suppresses the inflammatory responses by abrogating macrophage density in the injured tissue and by inhibiting cytokine release, extending the role the NRG-1/ErbB system during fibrosis. Beside inhibitory effects on fibroblasts, NRG-1 also has direct inhibitory actions on macrophages. This was endorsed by in vitro experiments showing strong inhibitory actions on the cytokine synthesis of macrophages. Subsequently, we aimed at analyzing the in vivo effect of ErbB4 gene deletion in fibroblasts and macrophages, the key effector cells contributing to the formation of a fibrotic scar. NRG-1 expression rapidly increased upon inducing myocardial fibrosis in C57Bl/6N mice with ATII, indicating a modulatory role of the NRG-1/ErbB pathway during the induction of myocardial fibrosis. To further examine this modulatory role of the NRG-1/ErbB system on fibroblasts and macrophages, we bred mice with fibroblast-specific (ErbB4F/+s100a4-Cre+) and myeloid-specific (ErbB4F/FLysM-Cre+/-) deletion of the ErbB4 gene. These transgenic mice showed an exaggerated fibrotic response of the myocardium to ATII. Interestingly, similar effects were observed in BLEO-induced skin and/or lung fibrosis. These observations point to a double counter-regulatory activity of the NRG-1/ErbB system on fibroblasts and macrophages.
Conclusion: NRG-1 has widespread anti-fibrotic and anti-inflammatory effects during tissue fibrosis by direct inhibitory effects on fibroblasts and macrophages. Furthermore, the NRG-1/ErbB4 pathway appears to be an intrinsic negative feedback system of inflammation and fibrogenesis during the natural progression of fibrosis.