Background: The extracellular matrix (ECM) provides structural and functional support for the myocardium, but myocardial infarction (MI) changes the composition of the ECM. One of the chief components of the ECM, hyaluronan (HA), accumulates after MI; however, specific biological actions of HA-particularly at the level of infiltrating immune cells and implications of such interactions on ventricular remodeling-have not been explored.
Goal: Because acute accumulation of HA coincides with macrophage infiltration after MI, we assessed the impact of HA on macrophage function.
Results: Compared to SHAM hearts, HA levels were elevated in both the infarct and remote regions of infarcted hearts. Because acute accumulation of HA coincides with macrophage infiltration after MI, we explored the implication of HA accumulation on various endpoints of macrophage function, including macrophage activation, phagocytosis, and efferocytosis. Our data suggests that exposing macrophages to HAHMW pushes macrophages toward a more pro-inflammatory phenotype as indicated by increased secretion of pro-inflammatory signals such as IL-2, IL-17, and IP-10. Our data also suggests that in the presence of HA, both macrophage efferocytosis and Fc-receptor dependent phagocytosis are suppressed. These results are unique to treatment with HAHMW, as similar results were not observed when cells were treated with HALMW. Using macrophages from Cd44-/- mice, we determined that while the impact of HAHMW on cytokine secretion does seem to be dependent in part on Cd44 expression, the impact on macrophage phagocytosis is independent. Since macrophage efferocytosis of dying cardiomyocytes and cellular debris is critical following MI, we believe that this response will prolong the resolution of inflammation and lead to maladaptive remodeling.
Conclusion: HA accumulates post-MI and may promote a pro-inflammatory phenotype in macrophages. Future studies will explore the extent to which post infarct HA accumulation regulates cardiac macrophage dynamics and function in vivo.
Keywords: Efferocytosis; Extracellular matrix; Immune cells; Phagocytosis.
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