Abstract
Phosphatidylserine (PS), a phospholipid predominantly found in the inner leaflet of eukaryotic cellular membranes, plays important roles in many biological processes. During apoptosis, the asymmetric distribution of phospholipids of the plasma membrane gets lost and PS is translocated to the outer leaflet of the plasma membrane. There, PS acts as one major “eat me” signal that ensures efficient recognition and uptake of apoptotic cells by phagocytes. PS recognition of activated phagocytes induces the secretion of anti-inflammatory cytokines like interleukin-10 and transforming grow factor-beta. Deficiencies in the clearance of apoptotic cells result in the occurrence of secondarily necrotic cells. The latter have lost the membrane integrity and release immune activating danger signals, which may induce inflammatory responses. Accumulation of dead cells containing nuclear autoantigens in sites of immune selection may provide survival signals for autoreactive B-cells. The production of antibodies against nuclear structures determines the initiation of chronic autoimmunity in systemic lupus erythematosus. Since PS on apoptotic cells is an important modulator of the immune response, natural occurring ligands for PS like annexinA5 have profound effects on immune responses against dead and dying cells, including tumour cells. In this review we will focus on the role of PS exposure in the clearance process of dead cells and its implications in clinical situations where apoptosis plays a relevant role, like in cancer, chronic autoimmunity, and infections. Relevance of other phospholipids during the apoptosis process is also discussed.
Highlights
The plasma membrane in eukaryotic cells is characterized by an asymmetrical distribution of phospholipids, the most abundant lipid components in membranes
PS can be present at the surface of exosomes derived from platelets and dendritic cells (DCs) [6], on viable monocytes [7], on the surface of mature macrophages [8], on nuclei expelled from erythroid precursor cells [9]; on activated B cells [10], in the nuclear matrix [11,12], and as soluble PS derived from cancer cells [13]
There are many open questions regarding the biology of “find me” signals that remain to be clarified: Are other phospholipids or its derivatives involved in the recruitment of phagocytes, which receptors and signaling pathways are implicated, and can “find me” signals be targeted for therapeutic purposes?
Summary
The plasma membrane in eukaryotic cells is characterized by an asymmetrical distribution of phospholipids, the most abundant lipid components in membranes. Aminophospholipids, like phosphatidylserine (PS) and phosphatidylethanolamine (PE), are generally enriched in the cytoplasmic leaflet, while phosphatidylcholine (PC), sphingomyelin (SM), and glycosphingolipids are mainly located on the exoplasmic leaflet. Minor phospholipids, such as phosphatidic acid and phosphatidylinositol (PI), are found on the cytoplasmic face. Such membrane asymmetry is widely observed in eukaryotes from yeast to mammalian cells [1,2]. In this review we will focus on the importance of PS exposure in the clearance process of dying cells and its implications in clinical situations where apoptosis plays a relevant role, like cancer, chronic autoimmunity, and infections. The relevance of other phospholipids during apoptosis and corpses removal process is discussed
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