Impaired Efferocytosis of Pericytes and Vascular Smooth Muscle Cells in Diabetic Retinopathy

During diabetic retinopathy (DR), cell death has been characterized in all of the major retinal cell types, but was observed initially in the microvasculature, particularly the mural cells: pericytes and vascular smooth muscle cells (VSMCs). Indeed, our ability to identify the mural cell corpses called “ghost cells” within the vascular basement membranes (BMs) in eyes of diabetic patients and animal models is indicative that removal of dead cells, or efferocytosis (EF), is dysfunctional during this disease. EF is the process whereby apoptotic cells are eliminated through phagocytic engulfment and digestion and is essential to maintain tissue integrity and immune homeostasis. The process occurs in three distinct phases: finding and recognition, engulfment, and digestion, under the direction of “find me” and “eat me” signals and a large array of their cognate receptors and bridging molecules. Efferocytosis can be performed by many cell types, but most efficiently by professional phagocytes, and with such rapidity that the process is extremely difficult to detect in healthy tissues. As delayed EF is a recognized cause of autoimmune and inflammatory disease, mural cell death in DR may create inflammatory foci in the neurovascular unit (NVU). Here we discuss the basic mechanisms of EF in the context of DR and the impact of diabetic metainflammation on EF effector cell dysfunction.