M2 Macrophage Exosomes Reverse Cardiac Functional Decline in Mice with Diet-Induced Myocardial Infarction by Suppressing Type 1 Interferon Signaling in Myeloid Cells.

Abstract

Effective treatment strategies to alleviate heart failure that develops as a consequence of myocardial infarction (MI) remain an unmet need in cardiovascular medicine. In this study, we uncover that exosomes produced by human THP-1 macrophages cultured with the cytokine IL-4 (THP1-IL4-exo), reverse cardiac functional decline in mice that developed MI in response to diet-induced occlusive coronary atherosclerosis. Therapeutic benefits of THP1-IL4-exo stem from their ability to drive transcriptional reprogramming of inflammatory responses in myeloid cells. Notably, repeated infusions of THP1-IL4-exo led to the suppression of Type 1 Interferon signaling in circulating Ly-6C^hi monocytes as well as in myeloid cells within the bone marrow and cardiac tissue. In vitro studies with primary macrophages stimulated with double-stranded DNA confirmed an ability for THP1-IL4-exo to confer suppression of Type 1 Interferon-mediated immune activation and inflammation. Collectively, these benefits contribute to the control of myelopoiesis, cardiac myeloid cell recruitment, and preserve populations of resident cardiac macrophages that together mitigate cardiac inflammation, adverse ventricular remodeling, and heart failure. Our findings introduce THP1-IL4-exo, one form of M2-macrophage exosomes, as novel anti-inflammatory and tissue repair therapeutics to preserve cardiac function post-MI.