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Apoptosis and necrosis differ in morphological, biochemical and immunological aspects, but both eventually result in engulfment of the dead cell or its remnants by a phagocyte. Apoptotic cells can be swallowed in one gulp due to the preserved impermeability of the plasma membrane. The cells may undergo secondary necrosis and lose plasma membrane integrity if clearance does not occur fast enough. Conclusion Secondary necrotic cells pose several problems for the body as follows: a) Necrotic cell clearance is pro-inflammatory due to danger signals leaking out of the cell. This is in strong contrast to the anti-inflammatory clearance of apoptotic cells. Exaggerated inflammation may cause tissue damage and exacerbate the course of various diseases. b) Chronic deficiencies in apoptotic cell clearance lead to an accumulation of late apoptotic and secondary necrotic cells. The persistent accessibility of otherwise occult intracellular antigens may challenge auto-tolerance and is a hallmark of systemic lupus erythematosus. c) Intracellular macromolecules that leak out of necrotic cells have to be cleared individually. In this review, we summarise the knowledge on clearance mechanisms for chromatin, neutrophil extracellular traps, ribonucleic acid and uric acid, and explain the possible implications if their clearance is insufficient. A potentially fatal outcome of massive leakage is the tumour lysis syndrome. Introduction Apoptotic cell death and clearance During physiological tissue turnover, billions of cells in the human body undergo apoptosis every day. The ‘programmed cell death’ is characterised by the systematic degradation of intracellular, potentially dangerous contents. Its features are condensation of chromatin, fragmentation of the nucleus and cytoskeletal remodelling. The latter leads to the formation of plasma membrane blebs and cell shrinkage1. A hallmark in contrast to necrosis is the preserved impermeability of the plasma membrane1. Regarding apoptosis, death is usually closely linked to burial, that is apoptotic cells are usually rapidly and efficiently engulfed by resident tissue macrophages. If professional phagocytes are locally missing, then many other cell types can function as non-professional phagocytes and serve the clearance of apoptotic cells2. Free apoptotic cells are therefore rarely observed in normal tissues3. Proper functioning of this clearance process is ensured by fine-tuned signalling mechanisms. Apoptotic cells release ‘find me’ signals into their vicinity to attract phagocytes. These molecules include proteins, like the covalently linked dimer of the ribosomal protein S19; nucleotides, like adenosine triphosphate (ATP) and uridine-5’-triphosphate (UTP); lysophosphatidylcholine and membrane-derived microblebs carrying intercellular adhesion molecule 3 (ICAM-3)4,5. Lactoferrin exerts a special role as a ‘keep out’ signal. It is so far the only known molecule secreted by apoptotic cells that inhibits neutrophil recruitment, in addition to its several anti-inflammatory effects6. Notably, signalling molecules do not passively leak out of apoptotic cells, but are released or secreted while the plasma membrane is still intact. Phosphatidylserine (PS) is the key ‘eat me’ signal that mediates the engulfment of apoptotic cells by phagocytes7. During apoptosis, PS is translocated from the inner to the outer leaflet of the plasma membrane. It can be recognised by macrophages directly via receptors, like brain angiogenesis inhibitor 1 (BAI-1) and members of the T cell Ig and mucin family (TIM). Milk fat globule-epidermal growth factor (EGF) factor 8, annexin A1 or other soluble bridging molecules can bind to PS and mediate the interaction between phagocyte and prey4,8. Further ‘eat me’ signals and the inactivation of ‘don’t eat me signals’ play additional roles in the engulfment process. The clearance of apoptotic cells is an everyday task in tissue homeostasis, and favourably proceeds in an immunologically silent way. Finally, apoptotic cells expose ‘tolerate me’ signals that suppress the secretion of proinflammatory cytokines, like tumour necrosis factor alpha (TNF-α), interleukin 1 (IL-1) and IL-12 by phagocytes. Furthermore, they induce the production of the anti-inflammatory mediators, such as transforming growth factor beta (TGF-β), IL-10 and prostaglandin E2 (PGE2)9,10. Notably, PGE2 is also released by apoptotic cells and induces an anti-inflammatory and tissue repair * Corresponding author Email: martin.herrmann@UK-erlangen.de † These authors contributed equally to this study. # These authors contributed equally to the senior authorship. Department of Internal Medicine 3, University of Erlangen-Nuremberg Ulmenweg 18, 91054 Erlangen, Erlangen, Germany Ce llu la r & M ol ec ul ar

No littering: The clearance of dead cells and leaking cellular contents and possible pathological complications