**1. Introduction**

In multicellular species, cell death and the efficient clearance of dying cells are fundamental processes that preserve homeostasis. Cells engage in their demise in virtually all physiological and most pathological scenarios through a controlled cascade of signaling events ('regulated' cell death) [1] Damaged or redundant cells die in a regulated manner and are replaced by new cells derived from progenitors of stem cells [2]. Cell death is essential for growth; during mammalian embryogenesis and development, billions of cells are destroyed in order to form new structures and sustain organ function [3, 4]. When addressing pathological events, including tissue damage and infections, significant numbers of cells often die. Cell death must be carefully controlled; extensive damage caused by heat, mechanical compression or osmotic pressure, for example, can cause necrosis of cells, release their intracellular content to the surrounding environment, and contribute to the activation of inflammatory immune pathways that can harm healthy cells and tissues surrounding them. In both homeostasis and disease, removal of cellular corpses is necessary. The phagocyte engulfment of dead cells, a multistep mechanism known as efferocytosis, enables cellular components to be recycled by multicellular organisms. Autoimmune diseases and other diseases may occur when the disposal of cell corpses is faulty. While the degradation and recycling of the mass of a cell are typical features in the clearance of any dead cell, certain cell clearance characteristics are specific to a particular mode of cell death. Depending on their mode of death, dying cells can expose and secrete signals that attract phagocytes, favor their swallowing, or encourage a return to tissue homeostasis. Via regulation of macrophage function following efferocytosis, different forms of cell death may also confer proinflammatory or anti-inflammatory signals. There are several cases in which uncoupled phenomena are cell death and corpse disposal, meaning cell death does not follow disposal immediately. The shedding of dead intestinal epithelial cells from the tip of the villus to the intestinal lumen 5 is one such example. Conversely, cells engulf and destroy healthy neighbouring cells in the course of entosis. Although the responsible mechanisms are usually different from those for the removal of dead cells, [5–11] shared aspects have been identified. Nonetheless, dying cells are easily cleared by efferocytosis in the vast majority of cases, and such uncoupled events are not further considered herein. Here we summarise our current understanding of the mechanisms of efferocytosis and how the physiology of the organism is affected by efferocytosis, including inflammation and adaptive immune response results. Every day, several hundred billion cells die and are replaced by newly formed cells. Senescent neutrophils die and are then phagocytized in the bone marrow, liver, and spleen by macrophages [7, 8], while senescent red blood cells are recognized and phagocytized by spleen and liver macrophages [7, 8]. In the small intestine, senescent enterocytes are shed into the intestinal lumen [11]. Cells infected with bacteria or viruses undergo autonomous necrosis of the cells or are destroyed by the immune system. Macrophages as a whole do not recognize these cells, and necrotic cells release materials that may activate the immune system. Inflammation caused by a bacterial or viral infection requires significant white blood cell development, and these cells rapidly die when the infection ceases. Additionally, by inhibiting the synthesis of purines, DNA, or RNA or by cross-linking or intercalating DNA, various anticancer drugs destroy tumour cells.

### **2. Programmed cell death**

Originally, programmed cell death in the sense of insect development was described by Lockshin and Williams [2]. Subsequently, Kerr et al. [12] noted two morphologically distinct forms of cell death in humans, apoptosis and necrosis, through ultrastructural study. The cells swell in necrosis, with the rupture of plasma membranes and release of cellular components; the cells shrink with integral yet ruffling plasma membranes in apoptosis, and nuclei are condensed and fragmented. To avoid the release of intracellular elements, apoptotic cells are rapidly phagocytized by macrophages. This mechanism prevents inflammatory factors from being released and is thus called the death of clean cells. "Programmed cell death" and "apoptosis" are also used synonymously, because apoptosis occurs in developing embryos or in cells that die under physiological conditions. The cell death occurring during inflammation or infection with a necrotic morphology was also found

to be programmed or regulated by gene products and was classified as necroptosis and pyroptosis [13]. In addition, non-apoptotic cell death was observed during the development of *Caenorhabditis elegans* [14] and *Drosophila metamorphosis* [15], suggesting that cell death can occur through a non-apoptotic mechanism in animal development. Programmed cell death should therefore not be used as a synonym for apoptosis; it should, as originally described, be reserved for the cell death that takes place in animal development [2].
