Eat-me signals

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Cells release eat-signals onto their surface to induce phagocytes to eat them Eat-me signal.pdf
Cells release eat-signals onto their surface to induce phagocytes to eat them

Eat-me signals are molecules exposed on the surface of a cell to induce phagocytes to phagocytose (eat) that cell. [1] [2] [3] Currently known eat-me signals include: phosphatidylserine, oxidized phospholipids, sugar residues (such as galactose), deoxyribonucleic acid (DNA), calreticulin, annexin A1, histones and pentraxin-3 (PTX3). [1] [2] [3] [4]

The most well characterised eat-me signal is the phospholipid phosphatidylserine. Healthy cells do not expose phosphatidylserine on their surface, whereas dead, dying, infected, injured and some activated cells expose phosphatidylserine on their surface in order to induce phagocytes to phagocytose them. [1] [2] [3] Most glycoproteins and glycolipids on the surface of our cells have short sugar chains that terminate in sialic acid residues, which inhibit phagocytosis, but removal of these residues reveals galactose residues (and subsequently N-acetylglucosamine and mannose residues) that can bind opsonins or directly activate phagocytic receptors. [4] [5] Calreticulin, annexin A1, histones, pentraxin-3 and DNA may be released by (and onto the surface of) dying cells to encourage phagocytes to eat these cells, thereby acting as self-opsonins. [4] Eat-me signals, or the opsonins that bind them, are recognised by phagocytic receptors on phagocytes, inducing engulfment of the cell exposing the eat-me signal. [1] [2]

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Microglia Glial cell located throughout the brain and spinal cord

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Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed by phagocytes. Different types of things ("targets") can be tagged by opsonins for phagocytosis, including: pathogens, cancer cells, aged cells, dead or dying cells, excess synapses, or protein aggregates. Opsonins help clear pathogens, as well as dead, dying and diseased cells.

Phagosome

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Annexin is a common name for a group of cellular proteins. They are mostly found in eukaryotic organisms.

Phospholipid scramblase

Scramblase is a protein responsible for the translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane. In humans, phospholipid scramblases (PLSCRs) constitute a family of five homologous proteins that are named as hPLSCR1–hPLSCR5. Scramblases are not members of the general family of transmembrane lipid transporters known as flippases. Scramblases are distinct from flippases and floppases. Scramblases, flippases, and floppases are three different types of enzymatic groups of phospholipid transportation enzymes. The inner-leaflet, facing the inside of the cell, contains negatively charged amino-phospholipids and phosphatidylethanolamine. The outer-leaflet, facing the outside environment, contains phosphatidylcholine and sphingomyelin. Scramblase is an enzyme, present in the cell membrane, that can transport (scramble) the negatively charged phospholipids from the inner-leaflet to the outer-leaflet, and vice versa.

In molecular biology, an annexin A5 affinity assay is a test to quantify the number of cells undergoing apoptosis. The assay uses the protein annexin A5 to tag apoptotic and dead cells, and the numbers are then counted using either flow cytometry or a fluorescence microscope.

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Annexin A5 Protein-coding gene in the species Homo sapiens

Annexin A5 is a cellular protein in the annexin group. In flow cytometry, annexin V is commonly used to detect apoptotic cells by its ability to bind to phosphatidylserine, a marker of apoptosis when it is on the outer leaflet of the plasma membrane. The function of the protein is unknown; however, annexin A5 has been proposed to play a role in the inhibition of blood coagulation by competing for phosphatidylserine binding sites with prothrombin and also to inhibit the activity of phospholipase A1. These properties have been found by in vitro experiments.

ICAM3 Mammalian protein found in Homo sapiens

Intercellular adhesion molecule 3 (ICAM3) also known as CD50, is a protein that in humans is encoded by the ICAM3 gene. The protein is constitutively expressed on the surface of leukocytes, which are also called white blood cells and are part of the immune system. ICAM3 mediates adhesion between cells by binding to specific integrin receptors. It plays an important role in the immune cell response through its facilitation of interactions between T cells and dendritic cells, which allows for T cell activation. ICAM3 also mediates the clearance of cells undergoing apoptosis by attracting and binding macrophages, a type of cell that breaks down infected or dying cells through a process known as phagocytosis, to apoptotic cells.

Signaling lymphocytic activation molecule (SLAM) is a family of genes. Homophilic binding between SLAMs is involved in cell-to-cell adhesion during antigen presentation.

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A tingible body macrophage (TBMs) is a type of macrophage predominantly found in germinal centers, containing many phagocytized, apoptotic cells in various states of degradation, referred to as tingible bodies. Tingible body macrophages contain condensed chromatin fragments.

In cell biology, efferocytosis is the process by which apoptotic cells are removed by phagocytic cells. It can be regarded as the 'burying of dead cells'.

Lysophosphatidylcholine

Lysophosphatidylcholines, also called lysolecithins, are a class of chemical compounds which are derived from phosphatidylcholines.

Apoptotic-cell associated molecular patterns (ACAMPs) are molecular markers present on cells which are going through apoptosis, i.e. programmed cell death. The term was used for the first time by C. D. Gregory in 2000. Recognition of these patterns by the pattern recognition receptors (PRRs) of phagocytes then leads to phagocytosis of the apoptotic cell. These patterns include eat-me signals on the apoptotic cells, loss of don’t-eat-me signals on viable cells and come-get-me signals ) secreted by the apoptotic cells in order to attract phagocytes. Thanks to these markers, apoptotic cells, unlike necrotic cells, do not trigger the unwanted immune response.

Phagoptosis is a type of cell death caused by the cell being phagocytosed by another cell, and therefore this form of cell death is prevented by blocking phagocytosis.

The KX Blood-group Antigen (KXA) Family (TC# 2.A.112) consists of transport proteins that are part of the TOG superfamily. The KX gene codes for a novel protein with characteristics of membrane transporters that has been proposed to be a Na+ -dependent neutral amine and/or oligopeptide transporter. It is predicted to be 444 amino acyl residues in length and exhibits 10 putative transmembrane α-helical segments. The KX blood group antigen mRNA expression pattern correlates with McLeod syndrome.

Kodimangalam S. Ravichandran is a U.S. immunologist and a leading researcher in the area of how we remove billions of dying cells in the body on a daily basis, and how such dead cell removal impacts many human inflammatory diseases. Dr. Kodi Ravichandran obtained his degree in Veterinary Medicine from Madras Veterinary College in 1987. During the last two years of Veterinary School, he became interested in the molecular biology of cellular processes, and how specific drugs function at a molecular level. This led to his pursuing a PhD in Molecular and Cell Biology at the University of Massachusetts at Amherst in the United States. For his doctoral work, he addressed how temporal gene expression and antibody specificities contribute toward the repertoire of B lymphocytes in various lymphoid organs in mice. Dr. Ravichandran then moved to at Dana-Farber Cancer Institute to pursue his post-doctoral research under the guidance of Dr. Steven Burakoff. Here, he focused on intracellular signaling in T cells, and addressed the role of adapter proteins, and published multiple high impact publications (1992-1996). He was also an instructor at Harvard Medical School.

Find-me signals are molecules released by a cell to attract phagocytes to that cell by chemotaxis, thereby increasing phagocytosis of the cell by phagocytes. Thus, when a cell releases a find-me signal, it attracts other cells to come and find it, and then eat it, thereby disposing of the cell. For example, cells undergoing apoptosis release ATP to attract macrophages to the apoptotic cell, which may then lead to phagocytosis of the apoptotic cell by the macrophage.

References

  1. 1 2 3 4 Ravichandran, Kodi S. (2011). "Beginnings of a Good Apoptotic Meal: The Find-Me and Eat-Me Signaling Pathways". Immunity. 35 (4): 445–455. doi:10.1016/j.immuni.2011.09.004. PMC   3241945 . PMID   22035837.
  2. 1 2 3 4 Park, Seung-Yoon; Kim, In-San (2017). "Engulfment signals and the phagocytic machinery for apoptotic cell clearance". Experimental & Molecular Medicine. 49 (5): e331. doi:10.1038/emm.2017.52. ISSN   1226-3613. PMC   5454446 . PMID   28496201.
  3. 1 2 3 Nagata, Shigekazu; Segawa, Katsumori (2021). "Sensing and clearance of apoptotic cells". Current Opinion in Immunology. 68: 1–8. doi:10.1016/j.coi.2020.07.007. PMID   32853880. S2CID   221360052.
  4. 1 2 3 Cockram, Tom O. J.; Dundee, Jacob M.; Popescu, Alma S.; Brown, Guy C. (2021). "The Phagocytic Code Regulating Phagocytosis of Mammalian Cells". Frontiers in Immunology. 12: 629979. doi: 10.3389/fimmu.2021.629979 . ISSN   1664-3224. PMC   8220072 . PMID   34177884.
  5. Kelley, Shannon M; Ravichandran, Kodi S (2021). "Putting the brakes on phagocytosis: "don't‐eat‐me" signaling in physiology and disease". EMBO Reports. 22 (6): e52564. doi:10.15252/embr.202152564. ISSN   1469-221X. PMC   8183410 . PMID   34041845.