Cardiac fibroblast pretreated by ANG II induced M1 phenotype macrophage selective apoptosis through TNF-TNFR1 and survival M1 conversion into M2 depended on Leptin-PI3K-Akt pathway

Abstract Inflammatory monocytes and tissue-resident macrophage are key regulators of tissue injury, would healing, organ remodeling and regeneration. After tissue injury, most monocytes and macrophages infiltrate into injury sites, undergo phenotypic and functional changes: differentiation into proinflammatory M1 phenotype and anti-inflammatory M2 in milieu. The reprogramming M1 and M2 macrophages involve in inflammatory initiation, development, resolution, and organ function remodeling, respectively. Disturbances in macrophage reprogramming can lead to aberrant repair or uncontrolled inflammatory response. Timely modulation of the reprogramming of macrophages is essential for the treatment of inflammatory diseases. Therefore, it becomes fatal to clarify the M1 fate or the function shift of M1 and M2 during tissue injury development. In the present work, we demonstrated that cardiac fibroblasts (MCF) pretreated by angiotensin II (ANG II) (myofibroblast, MFB) could not only promote macrophage reprogramming toward M1 but also induced M1 macrophage selective apoptosis through TNF/TNFR1 axis independent on Fas/FasL; furthermore, in co-culturing system, leptin produced by MFB or M1/M2 cells could promote the survival M1 conversion into M2 macrophage via PI3K/Akt pathway. In vivo, TNF-alpha blockade significantly ameliorated experimental autoimmune myocarditis (EAM) development. Our data highlighted a novel mechanism about the fates of M1 macrophage in inflammatory diseases and our data also suggested a potential check point for inflammatory disease therapy target on macrophage.