Death begets a new beginning

Abstract

Cell death is a perpetual feature of tissue microenvironments; each day under homeostatic conditions, billions of cells die and must be swiftly cleared by phagocytes. However, cell death is not limited to this natural turnover-apoptotic cell death can be induced by infection, inflammation, or severe tissue injury. Phagocytosis of apoptotic cells is thus coupled to specific functions, from the induction of growth factors that can stimulate the replacement of dead cells to the promotion of tissue repair or tissue remodeling in the affected site. In this review, we outline the mechanisms by which phagocytes sense apoptotic cell death and discuss how phagocytosis is integrated with environmental cues to drive appropriate responses.

Keywords: apoptosis; homeostatic clearance; inflammation; macrophages; phagocytosis; tissue repair.

Figure 1. Apoptotic cell death and subsequent clearance regulates compensatory proliferation during development and homeostasis

Upon cell death, macrophages or other phagocytic cells sense the apoptotic cell and then release molecules, like mitogens and growth factors, which result in the proliferation or differentiation of cells to replace those that are dying. Factors released from apoptotic cells themselves may directly stimulate proliferation of surrounding cells helping to replenish adjacent populations. Other neighboring cells may likewise serve as mediators.

Figure 2. Phagocytic clearance is critical for homeostatic tissue function across various systems

(A) For proper development of spermatozoa from spermatogonia (right), Sertoli cells must also engulf the many germ cells that undergo apoptosis following defective differentiation. (B) Photoreceptor outer segments are routinely shed following exposure to light and are cleared by retinal pigment epithelial cells. (C) Macrophage engulfment of extruded nuclei from developing erythroblasts is necessary for erythrocyte maturation. (D) The subventricular zone (SVZ) is one site of neurogenesis in the adult brain, with successfully differentiating neurons migrating along the rostral migratory stream (RMS) and reaching the olfactory bulb (OB). Phagocytes, including microglia, are involved in clearing apoptotic neuroblasts, as well as some viable neuroblasts, that result from this neurogenesis.

Figure 3. Unscheduled apoptotic cell death promotes distinct anti-inflammatory and tissue repair programs in macrophages

(A) Macrophages sense homeostatic turnover of apoptotic neutrophils, remove the corpses to avoid secondary necrosis, and respond by initiating replenishment of these cells. (B) In the context of an infection or injury, pathogen- or damage-associated molecular patterns (PAMPs, DAMPs) induce a pro-inflammatory response by macrophages. Additional recognition of apoptotic cells has an immunosuppressive effect, and contemporaneously promotes an anti-inflammatory program. (C) In contrast, engulfment of apoptotic cells in the presence of IL-4/IL-13 results in a distinct tissue repair response, including the potentiation of Retnla and Chil3 expression.