Modulation of Cardiac Macrophages with Interleukin-4 as a Strategy of Infarct Healing

Abstract

Cardiovascular disease is the leading cause of death in the United States accounting for approximately 1 in every 3 deaths. Many efforts have been made to reduce the mortality rate after a MI by analyzing and possibly manipulating the immune system response following an MI. Immediately after an MI has occurred, pro-inflammatory macrophages (M1) are recruited at the affected site. M1 are responsible for clearing dead cells and debris. Following the M1 response, wound healing (M2) macrophages, responsible for angiogenesis and cell regeneration, are recruited at the site. Although the M1 subset is required for proper wound healing, prolonged activation of this macrophage subset attributes to cell fibrosis and tissue scaring. This study initially aims in modulation of macrophages to a M2 phenotype utilizing IL-4 after an MI occurs. The secondary aim is delivery of IL-4 to the heart site utilizing a PEG-MAL hydrogel. This study could prove that delivery of IL-4 to the heart could suppress inflammatory signals after an MI and lead to a healing response. In vitro studies in RAW and bone marrow macrophages indicated IL-4 leads to an increase in the MRC1 and Arginase 1, M2 markers, and macrophages stimulated with lipopolysaccharide (LPS) and interferon gamma increased M1 markers nitrite and tumor necrosis factor alpha. The addition of both M1 and M2 stimuli simultaneously increased Arginase 1 and nitrite production significantly. The IL-4 treated media from the In vitro macrophages increased cardiac progenitor cell migration by 70% relative to the control. This shows that IL-4 differentiated macrophages can communicate with other cells crucial to healing. Knowledge of the effects of IL-4 after a heart attack could greatly improve cardiac cell regeneration and lead to better patient health.