1-JS-Dissertation-R-final-1.4.18.pdf
Creators: name: Jianrui Song
Publisher: name: Health Research Alliance
Year: 2019
Subjects: subject: 110201 Cardiology (incl. Cardiovascular Diseases)
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine

description: p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px Helvetica} Cardiovascular disease is the leading cause of death, and understanding the pathophysiological changes that occur in response to injury is important for identifying novel drug targets and developing improved therapeutics. The process of cardiovascular remodeling, which occurs after injury and includes structural and functional changes has been identified as a target for therapeutic intervention. p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px Helvetica} Reprogramming macrophages towards a reparative phenotype in cardiovascular remodeling is a potential therapeutic approach. Interleukin-4 receptor (IL4R) signaling is an inducer of alternatively activated macrophages (AAM or M2), and M2 macrophages are critically involved in inflammation resolution, tissue repair and pathological development of fibrosis. IL-4 administration can be beneficial, but the important IL-4 responsive cell types mediating the protection have not been identified. We hypothesized that macrophages are the critical target cell type of IL-4, and macrophage IL4R signaling plays an important role in cardiovascular remodeling by controlling macrophage polarization. In order to test this hypothesis, we generated myeloid (macrophage/monocyte and neutrophil)-specific IL-4 receptor α knockout (MyIL4RαKO) mice. Bone marrow derived macrophages from MyIL4RαKO mice showed a significantly blunted response to the M2 macrophage stimulus IL-4 and a markedly augmented response to the M1 macrophage stimulus LPS, indicating the importance of IL4Rα signaling in macrophage polarization in vitro. In addition, significant decreases of M2 macrophage markers at basal levels were shown in the heart suggesting that endogenous IL4R is required for appropriate macrophage polarization of resident cardiac macrophages.In cardiac remodeling post myocardial infarction (MI), the infarct size of MyIL4RαKO mice at 1 week post-MI was significantly smaller than that of control mice and infarct thickness at 3 weeks was significantly increased, indicating the involvement of myeloid IL4Rα signaling in cardiac remodeling post-MI. No changes in collage deposition were detected within the infarct, but there was evidence of an important role for endogenous cytokine action at the myeloid IL-4R since there was greater cardiac dysfunction in MyIL4RαKO mice.Surprisingly, IL4Rα knockout in myeloid cells did not change the percentage or number of M2 macrophages in infarct tissues post-MI. This does not support the hypothesis that IL4Rα signaling mediates cardiac remodeling via its control of macrophage polarization, but rather that the effect on myeloid phenotype is considerably subtler.In angiotensin II and high salt-induced hypertensive cardiovascular injury, cardiac and vascular fibrosis was substantially decreased in MyIL4RαKO mice. This corresponded to significant changes in fibrosis-related signaling pathways including TGFβ, Gal3 and BMP9 signaling. MyIL4RαKO mice also showed significantly increased mRNA expression of reactive oxygen species (ROS) generation related genes. This suggests that myeloid IL4Rα signaling significantly alters cardiovascular remodeling post hypertensive injury by regulating collagen accumulation and ROS generation. Similar to what we found in the MI model, ablation of IL4Rα in myeloid cells did not induce changes in the polarization of M2 macrophages in the heart and aorta during hypertensive injury. This suggests that the changes in cardiovascular remodeling may not be attributed to a simple alteration in global macrophage polarization.In conclusion, results from both injury models suggest that myeloid cells are critical targets of endogenous IL4Rα signaling, and myeloid IL4Rα signaling is very important in modulating cardiovascular remodeling post injury. However, the mechanism by which myeloid IL4Rα signaling regulates cardiovascular remodeling is not simply through a global change in M2 macrophage polarization in vivo, and the exact mechanism needs to be determined further. p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px Helvetica} p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px Helvetica} p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px Helvetica}