17th European Heart Disease and Heart Failure Congress
University of Michigan, USA
Title: Myeloid-specific IL4 receptor alpha knockout increases adverse cardiac remodeling post myocardial infarction
Biography: Jianrui Song
Myocardial infarction (MI) elicits inflammatory reactions that are orchestrated by a wide range of immune cells including macrophages. Reprogramming macrophages towards a resolving and reparative phenotype is a potential therapeutic approach for MI. However, how to modify macrophages in order to improve cardiac injury is not clear. Interleukin 4 receptor alpha (IL4Ra) activation is one of the major alternative activated macrophage (also names M2 macrophage) inducers, so IL4Ra is a potential macrophage modifier. Here, we knocked out IL4Ra from myeloid cells to determine how IL4Ra signaling is involved in cardiac remodeling post MI. Myeloid-specific IL4Ra knockout (MyIL4RaKO) did not show significant change in cardiac hypertrophy and interstitial fibrosis. There was decreased infarct size at one week post MI, but by three weeks there was no significant difference in infarct size. We saw significantly increased infarct thickness and perivascular fibrosis at three weeks, indicating the involvement of IL4Ra signaling in cardiac remodeling. Importantly, along with these significant changes in cardiac remodeling, MyIL4RaKO mice showed significantly decreased cardiac function at three weeks post MI. IL4Ra signaling was significantly inactivated in macrophages; however no change was shown in macrophage polarization in heart tissues post MI. In conclusion, IL4Ra signaling in myeloid cells is critical in maintaining proper cardiac remodeling and cardiac function post MI, which suggests the potential of modifying macrophages through enhancing IL4Ra signaling as a therapeutic strategy for MI.
1.Manabu Shiraishi, Yasunori Shintani, Yusuke Shintani, Hidekazu Ishida, Rie Saba, et al, and Ken Suzuki. Alternatively activated macrophages determine repair of the infarcted adult murine heart. J Clin Invest. 2016 Jun 1;126(6):2151-66.
2.Janine Woytschak, Nadia Keller, Carsten Krieg, Daniela Impellizzieri, Robert W. Thompson, et al, and Onur Boyman. Type 2 Interleukin-4 Receptor Signaling in Neutrophils Antagonizes Their Expansion and Migration during Infection and Inflammation. Immunity. 2016 Jul 19;45(1):172-84.
3. Johanna A. Knipper, Sebastian Willenborg, Ju¨ rgen Brinckmann, Wilhelm Bloch, Tobias Maaß, et al, and Sabine A. Eming.Interleukin-4 Receptor alpha Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair. Immunity. 2015 Oct 20;43(4):803-16.
4.Slava Epelman, Kory J. Lavine, Anna E. Beaudin, Dorothy K. Sojka, Javier A. Carrero, Boris Calderon, Thaddeus Brija, Emmanuel L. Gautier, Stoyan Ivanov, Ansuman T. Satpathy, Joel D. Schilling, et al, and Douglas L. Mann. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity. 2014 Jan 16;40(1):91-104.
5.Michael G. Usher, Sheng Zhong Duan, Christine Y. Ivaschenko, Ryan A. Frieler, Stefan Berger, Günther Schütz, Carey N. Lumeng, and Richard M. Mortensen. Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice. J Clin Invest. 2010 Sep;120(9):3350-64.