ABSTRACT
Macrophages release soluble mediators following efferocytic clearance of apoptotic cells to facilitate intercellular communication and promote the resolution of inflammation. However, whether inflammation resolution is modulated by extracellular vesicles (EVs) and vesicular mediators released by efferocytes is not known. We report that efferocyte-derived EVs express prosaposin, which binds to macrophage GPR37 to increase expression of the efferocytosis receptor Tim4 via an ERK-AP1-dependent signaling axis, leading to increased macrophage efferocytosis efficiency and accelerated resolution of inflammation. Neutralization and knockdown of prosaposin or blocking GRP37 abrogates the pro-resolution effects of efferocyte-derived EVs in vivo. Administration of efferocyte-derived EVs in a murine model of atherosclerosis is associated with an increase in lesional macrophage efferocytosis efficiency and a decrease in plaque necrosis and lesional inflammation. Thus, we establish a critical role for efferocyte-derived vesicular mediators in increasing macrophage efferocytosis efficiency and accelerating the resolution of inflammation and tissue injury.
Subject(s)
Extracellular Vesicles , Saposins , Animals , Mice , Apoptosis , Extracellular Vesicles/metabolism , Inflammation/metabolism , Macrophages/metabolism , Phagocytosis , Saposins/metabolism , Receptors, G-Protein-Coupled/metabolismABSTRACT
Phagocytic clearance of dead cells and debris is critical for inflammation resolution and maintenance of tissue homeostasis. Consequently, defective clearance of dead cells and debris is associated with initiation and exacerbation of several autoimmune disorders and chronic inflammatory diseases such as atherosclerosis. The progressive loss of dead cell clearance capacity within the atherosclerotic plaque leads to accumulation of necrotic cells, chronic non-resolving inflammation, and expansion of the necrotic core, which triggers atherosclerotic plaque rupture and clinical manifestation of acute thrombotic cardiovascular adverse events. In this review, we describe the fundamental molecular and cellular mechanisms of dead cell clearance and how it goes awry in atherosclerosis. Finally, we highlight novel therapeutic strategies that enhance dead cell and debris clearance within the atherosclerotic plaque to promote inflammation resolution and atherosclerotic plaque stabilization.
Subject(s)
Atherosclerosis/pathology , Inflammation/pathology , Macrophages/pathology , Phagocytosis , Plaque, Atherosclerotic , Animals , Anti-Inflammatory Agents/therapeutic use , Atherosclerosis/drug therapy , Atherosclerosis/immunology , Atherosclerosis/metabolism , Cell Death , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/metabolism , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Necrosis , Phagocytosis/drug effectsABSTRACT
Colony stimulating factors (CSFs) play a central role in the development and functional maturation of immune cells besides having pleiotropic effects on cells of the vascular wall. The production of CSFs is induced by multiple atherogenic and inflammatory stimuli and their expression levels are often correlated positively with advanced atherosclerotic plaques and adverse cardiovascular events in humans suggesting that CSFs play a critical role in the pathophysiology of atherosclerosis progression. Interestingly, recombinant CSFs as well as anti-CSFs are being increasingly used for diverse clinical indications. However, the effect of these novel therapeutics on atherosclerotic plaque progression is not well understood. Herein, we summarize the currently available literature on the complex role of CSFs in various stages of atherosclerosis and emphasize the necessity for conducting further mechanistic studies in animal models of atherosclerosis as well as the need for evaluating the cardiovascular safety of CSF-based therapies in humans.