Efferocytosis Signaling in the Regulation of Macrophage Inflammatory Responses

Abstract

Since the pioneering work of Elie Metchnikoff and the discovery of cellular immunity, the phagocytic clearance of cellular debris has been considered an integral component of resolving inflammation and restoring function of damaged and infected tissues. We now know that the phagocytic clearance of dying cells (efferocytosis), particularly by macrophages and other immune phagocytes, has profound consequences on innate and adaptive immune responses in inflamed tissues. These immunomodulatory effects result from an array of molecular signaling events between macrophages, dying cells, and other tissue-resident cells. In recent years, many of these molecular pathways have been identified and studied in the context of tissue inflammation, helping us better understand the relationship between efferocytosis and inflammation. We review specific types of efferocytosis-related signals that can impact macrophage immune responses and discuss their relevance to inflammation-related diseases.

Figure 1. Immunomodulatory roles of efferocytosis signals

Depiction of the three key stages of efferocytosis (dashed boxes) with detailed illustrations showing some of the known signaling molecules/pathways relevant to immune modulation for each of the three stages. The lower table indicates some of the key effects of these efferocytosis signaling mechanisms on: immune signaling in phagocytes, production of immune mediators, and some of the prominent immune outcomes of the indicated molecules/pathways. Arrows in the table indicate whether signaling via these pathways generally increases or decreases the effects listed. Please note this diagram represents only a portion of the efferocytosis signals and their immunoregulatory effects that have been described. More comprehensive lists of these signaling pathways can be found in references , . MMP (matrix metalloprotease) PS (PtdSer), RTK (receptor tyrosine kinase), ITIM (immune-tyrosine based inhibitory motif).