Efferocytosis and Outside-In Signaling by Cardiac Phagocytes. Links to Repair, Cellular Programming, and Intercellular Crosstalk in Heart

Abstract

Phagocytic sensing and engulfment of dying cells and extracellular bodies initiate an intracellular signaling cascade within the phagocyte that can polarize cellular function and promote communication with neighboring non-phagocytes. Accumulating evidence links phagocytic signaling in the heart to cardiac development, adult myocardial homeostasis, and the resolution of cardiac inflammation of infectious, ischemic, and aging-associated etiology. Phagocytic clearance in the heart may be carried out by professional phagocytes, such as macrophages, and non-professional cells, including myofibrolasts and potentially epithelial cells. During cardiac development, phagocytosis initiates growth cues for early cardiac morphogenesis. In diseases of aging, including myocardial infarction, heightened levels of cell death require efficient phagocytic debridement to salvage further loss of terminally differentiated adult cardiomyocytes. Additional risk factors, including insulin resistance and other systemic risk factors, contribute to inefficient phagocytosis, altered phagocytic signaling, and delayed cardiac inflammation resolution. Under such conditions, inflammatory presentation of myocardial antigen may lead to autoimmunity and even possible rejection of transplanted heart allografts. Increased understanding of these basic mechanisms offers therapeutic opportunities.

Neutrophil–macrophage cooperation and its impact on tissue repair

“…Furthermore, molecules released by neutrophils such as neutrophil gelatinase‐associated lipocalin can enhance efferocytosis by increasing the expression of the phosphatidylserine receptor MER proto‐oncogene, tyrosine kinase on macrophages . More recently, necroptosis, a regulated, nonapoptotic form of necrotic cell death has been shown to cause expression of “eat me signals” by neutrophils, thus enhancing efferocytosis by macrophages and improving the outcome after myocardial injury …”

“…44 More recently, necroptosis, a regulated, nonapoptotic form of necrotic cell death has been shown to cause expression of "eat me signals" by neutrophils, thus enhancing efferocytosis by macrophages and improving the outcome after myocardial injury. 45,46…”

The Role of Leukocytes in Diabetic Cardiomyopathy

“…These traits are significantly correlated with increased blood glucose levels ( Jakelic et al, 1995 ) and reversed by decreasing blood glucose levels in both humans ( Jakelic et al, 1995 ) and rats ( Alba-Loureiro et al, 2006 ). Normally in injured tissue, macrophages engulf apoptotic cells and cellular debris to reduce inflammation, a phenomenon called efferocytosis ( DeBerge et al, 2017 ). Several molecular processes contribute to this mechanism and in particular the metalloproteinase disintegrin and metalloproteinase domain-containing protein 9 (ADAM-9) was shown to be upregulated in macrophages under conditions of high glucose, secondary to decreased expression of miR-126, which increased MER proto-oncogene, tyrosine kinase (MerTK) cleavage to ultimately reduce efferocytosis ( Suresh Babu et al, 2016 ).…”

Cardiomyocytes and Macrophages Discourse on the Method to Govern Cardiac Repair

“…These cardiac myofibroblasts secrete MFG-E8 promoting efferocytosis and acquisition of anti-inflammatory properties ( 58 ). Communication between professional and non-professional phagocytes likely coordinates phagocytosis of dying cells in the vicinity of the damage ( 59 ). As a prototypic example, in epithelial tissue, following clearance of apoptotic cells, macrophages release soluble growth factors, such as insulin-like growth factor 1, which redirect the phagocytosis of neighbor epithelial cells toward uptake of smaller vesicular components ( 60 ).…”