Abstract
The prompt and efficient clearance of unwanted and abnormal cells by phagocytes is termed efferocytosis and is crucial for organism development, maintenance of tissue homeostasis, and regulation of the immune system. Dying cells are recognized by phagocytes through pathways initiated via “find me” signals, recognition via “eat me” signals and down-modulation of regulatory “don’t eat me” signals. Pathogen infection may trigger cell death that drives phagocytic clearance in an immunologically silent, or pro-inflammatory manner, depending on the mode of cell death. In many cases, efferocytosis is a mechanism for eliminating pathogens and pathogen-infected cells; however, some pathogens have subverted this process and use efferocytic mechanisms to avoid innate immune detection and assist phagocyte infection. In parallel, phagocytes can integrate signals received from infected dying cells to elicit the most appropriate effector response against the infecting pathogen. This review focuses on pathogen-induced cell death signals that drive infected cell recognition and uptake by phagocytes, and the outcomes for the infected target cell, the phagocyte, the pathogen and the host.
Highlights
To maintain and protect themselves, multicellular organisms remove dead and dying cells arising during normal tissue development and function [1] or triggered by infection or sterile inflammation [2]
As described earlier, subversion of efferocytic mechanisms via (i) the Trojan-horse type of strategy, (ii) cell-free microorganisms expressing or hijacking PS-containing membrane, and (iii) triggering of anti-inflammatory programs in macrophages by efferocytosis of apoptotic cells contributes to immune evasion and pathogen persistence
Therapeutic intervention in efferocytic pathways may well be a rational approach to reducing infection by certain pathogens, but care must be exercised to avoid perturbing the fine balance between homeostasis and deleterious inflammation
Summary
To maintain and protect themselves, multicellular organisms remove dead and dying cells arising during normal tissue development and function [1] or triggered by infection or sterile inflammation [2]. Phagocytosis is defined as engulfment of particulate matter of >0.5–1 μm [7, 8] and is mediated by both professional and non-professional phagocytic cell types. “Efferocytosis” is a term describing the engulfment by phagocytes of dying and dead cells and their debris [11, 12] and demonstrates features of both conventional phagocytosis and the fluid-phase uptake mechanism macropinocytosis [13,14,15], resulting in uptake into “spaceous phagosomes” [15]. The term efferocytosis distinguishes recognition and engulfment of dead and dying cells from phagocytosis of other objects [12, 16], we are unaware of specific mechanistic differences that discriminate between the two processes. The initial definition of efferocytosis related to clearance of apoptotic cells [15], but this has more recently been widened to include other modes of cell death [17, 18]
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