Our findings identified IL4-polarized macrophages (IL4-exo), commonly known as “M2-macrophages” as a source of anti-inflammatory exosomes. MicroRNA cargo present in IL4-exo were identified as a source of their protective signaling properties. The microRNA enriched in IL4-exo robustly increased mitochondrial respiration, oxidative phosphorylation and suppressed inflammatory signaling by communicating this cluster of microRNA to recipient cells that reprogrammed bioenergetic metabolism.
Beyond exerting an ability to suppress NF-kB activity in recipient myeloid cells, our studies uncovered a capacity for IL4-exo to augment mitochondrial metabolism and oxidative phosphorylation to fuel anti-inflammatory activities. IL4-exo were shown to potently suppress the process of hematopoiesis and thereby restrict the number of immune cells in the circulation of mice with hyperlipidemia. The immunometabolic control of immunity by IL4-exo potently induces the resolution of atherosclerosis in mice fed a diet rich in fat.
Ongoing studies of IL4-exo examine their capacity to induce pro-resolution pathways in lesional macrophages to drive the process of atherosclerosis regression.