IL-18 Promotes Erythrophagocytosis and Erythrocyte Degradation by M1 Macrophages in a Calcific Microenvironment

Background: Calcific aortic-valve disease (CAVD) is the most common cause of aortic valve replacement in developed countries. Intraleaflet hemorrhage has been found to be positively correlated with the progression of CAVD. Although most research has focused on erythrocyte degradation products, which promote progression of CAVD, the process of erythrophagocytosis and erythrocyte degradation by macrophages in intraleaflet hemorrhage areas has remained unexplored. Methods: The erythrocyte degradation products of aortic valve specimens were detected by Perls' staining and quantified. The gene and protein expression levels of interleukin (IL)-18 in THP-1-polarized macrophages cultured in osteogenic medium were tested. We also quantified the iron and heme degraded by macrophages and analyzed the expression of ferroportin (FPN) and heme oxygenase-1 (HO-1) in the osteogenic medium. Furthermore, we tested the mRNA and protein levels of osteoblast markers in valve interstitial cells after co -culture with M1 macrophages treated with IL-18 and erythrocytes. Results: Our experiments demonstrated that IL-18 activates HO-1 and FPN to promote erythrophagocytosis and erythrocyte degradation by macrophages in a calcific microenvironment via p38 and Erk1/2. We also found that the calcific microenvironment promotes IL-18 mRNA and protein expression in THP-1-polarized macrophages. Conclusions: In conclusion, IL-18 promotes M1 macrophage-mediated erythrophagocytosis and erythrocyte degradation by regulating the activation of HO-1 and FPN via p38 and Erk1/2 in a calcific microenvironment.

Automated summary

Research suggests that IL-18 promotes M1 macrophage-mediated erythrophagocytosis and erythrocyte degradation in a calcific microenvironment by regulating the activation of HO-1 and FPN via p38 and Erk1/2. Additionally, the calcific microenvironment can enhance the expression of IL-18 in THP-1-polarized macrophages.