INVESTIGATING THE IMPACTS OF MAST CELLS AND INTERLEUKIN-33 IN RESOLUTION OF INFLAMMATION AND CARDIAC FIBROSIS

Abstract

Cardiac fibrosis is characterized by excessive extracellular matrix deposition and tissue remodeling that leads to heart failure. Chronic inflammation promotes cardiac fibrosis and occurs after initial inflammatory responses to damage that are not effectively resolved. Mast cells are resident innate immune cells present in virtually all body tissues that act as sentinels to damage. Mast cells robustly respond to interleukin (IL)-33, a damage associated molecular pattern released upon stromal cell death. IL-33 exerts cytokine effects upon release via signaling through its cognate receptor ST2 to promote type 2 immune responses. We hypothesized that mast cells prevent excessive remodelling in the heart that leads to fibrosis via an IL-33-dependent mechanism. This hypothesis has been examined using human and mouse models. Atrial tissues from human cardiac surgery patients were assessed for mast cells, in relation to fibrosis, and clinical outcomes. We observed that patients with high mast cell density had lower atrial collagen content and improved functional outcomes post-operative. IL-33 did not have a role at this later stage in remodelling. In response to IL-33 in vitro, human mast cells produced a number of mediators of relevance to angiogenesis, such as vascular endothelial growth factor-A and urokinase plasminogen activator, but not those classically associated with fibrosis or inflammation. Finally, a mouse model of efferocytosis was employed, to determine impacts of IL-33 on inflammation resolution. IL-33 administration to the peritoneal cavity led to increased populations of macrophages bearing the efferocytosis receptor MerTK. Additionally, IL-33 promoted efferocytosis when apoptotic cells were introduced. This was not a mast cell dependent process. Through studies of human atrial tissues and related model systems, we have identified a novel association between mast cells, IL-33 and the resolution of cardiac fibrosis. Mast cell-derived angiogenic mediators identified in vitro may be relevant in this system. Our in vivo efferocytosis model can inform future work on inflammation resolution with relevance to the heart and other inflammatory sites. This work demonstrates the complexity of the cell types, mediators and interactions involved in a disease process such as cardiac fibrosis and has provided mechanisms to inform the development of more effective therapies.