Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Clearance of Dying Cells in Healthy and Diseased Immune Systems What do we mean when we write “senescence,” “apoptosis,” “necrosis,” or “clearance of dying cells”? DrorMevorach, Uriel Trahtemberg, Alon Krispin, Mizhir Attalah, Jonathan Zazoun, Adi Tabib, Amir Grau, and Inna Verbovetski-Reiner The Laboratory for Cellular and Molecular Immunology, Rheumatology Research Center, Hebrew University and Hadassah University Medical Center, Jerusalem, Israel Address for correspondence: Dror Mevorach, M.D., Rheumatology Research Center, Department of Medicine, Hadassah and the Hebrew University, POB 12000, Kiryat Hadassah, Jerusalem 91200, Israel. mevorachd@hadassah.org.il The clearance of dying cells has become an important field of research. Apart from a significant increase in our understanding of the mechanisms for uptake, cell clearance is a basic mechanism in tissue homeostasis, cancer, resolution of inflammation, induction of tolerance, and autoimmunity. Phagocytosis of dying cells is a complex process, involving many interacting molecules on the dying cell and the phagocyte, and in the microenvironment. Although much is known on the subject, there are many questions and unknown variables that remain under investigation. Naturally, different terms were developed, among which some are misused, leading sometimes to pseudoconflicts of understanding. Several receptors were described as “phosphatidylserine receptor: are they all equal?” We will revise terms such as apoptosis, primary and secondary necrosis, lysed cells, senescent cells, clearance of apoptotic cells, efferocytosis, and more. We will try to point out misnomers, misunderstandings, and contradictions, and to define a consensual vocabulary. Keywords: apoptosis; necrosis; senescence; clearance of apoptotic cells Introduction The clearance of dying cells has become an impor- tant field of research. Apart from a significant in- crease in our understanding of the mechanisms for uptake, cell clearance is a basic mechanism in tis- sue homeostasis, cancer, resolution of inflamma- tion, induction of tolerance, and autoimmunity. Programmed cell death (PCD) refers to the process where a cell, once the decision to die is taken, under- goes a series of defined molecular transformations that bring about an ordered demise. 1–3 The terms apoptosis and PCD were once used interchangeably. However, today the term PCD can be subdivided to at least three death pathways: apoptosis, necrosis, 1–5 and autophagy. 6,7 The concept of PCD does not stand on its own and demands a further explanation of specific patterns. Issues relevant to PCD include the following: what was the trigger leading to the de- cision to die, what is the pattern involved, how long does the process take, what other programs are acti- vated, and more. In some circumstances, cells may switch from apoptosis to necrosis or autophagy, and vice versa. What do we really mean? Apoptosis This is a type of cell death that is defined, first and foremost, by a set of morphological changes (not always completely present): nuclear shrink- age and fragmentation, chromatin condensation, membrane blebbing, and the release of apoptotic bodies. 8 Another important aspect of apoptosis is that it is an active, ATP-dependent cell death, lead- ing to its common designation as “cellular suicide.” It requires energy for completion and involves a large set of events as it progresses. 2 Interestingly, some events during apoptosis are of functional im- portance for the organism and not directly related to its demise. 9 The main molecular events during apoptosis are now known, although many details doi: 10.1111/j.1749-6632.2010.05774.x Ann. N.Y. Acad. Sci. 1209 (2010) 1–9 c  2010 New York Academy of Sciences. 1