Phagoptosis

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Phagoptosis is a type of cell death caused by the cell being phagocytosed (i.e. eaten) by another cell, and therefore this form of cell death is prevented by blocking phagocytosis. [1] [2]

Contents

Phagocytosis of an otherwise-viable cell may occur because the cell is recognised as stressed, activated, senescent, damaged, pathogenic or non-self, or is misrecognised. Cells are phagocytosed as a result of: i) expressing eat-me signals on their surface, ii) losing don’t-eat-me signals, and/or iii) binding of opsonins. It is clear that otherwise-viable cells can expose/bind such phagocytosis-promoting signals as a result of cell stress, activation or senescence. Phagoptosis is probably the most common form of cell death in the body as it is responsible for erythrocyte turnover. And there is increasing evidence that it mediates physiological death of neutrophils, T cells, platelets and stem cells, and thereby regulates inflammation, immunity, clotting and neurogenesis. Phagoptosis is a major form of host defence against pathogens and cancer cells. However, recent evidence indicates that excessive phagoptosis may kill host cells in inflammatory conditions, contributing to haemophagic conditions, and neuronal loss in the inflamed brain.

Mechanism

Phagoptosis is normally caused by: the cell exposing on its surface so-called "eat-me" signals, and/or the cell no longer exposing "don't-eat-me" signals and/or the cell being opsonised i.e. binding soluble proteins that tag the cell for phagocytosis. For example, phosphatidylserine is an "eat-me" signal that, when exposed on the surface of a cell, triggers phagocytes (i.e. cells that eat other cells) to eat that cell. Phosphatidylserine is normally found on the inside of healthy cells, but can become exposed on the surface of dying, activated or stressed cells. Phagocytosis of such cells requires specific receptors on the phagocyte that recognise either phosphatidylserine directly or opsonins bound to the phosphatidylserine or other "eat-me" signals, such as calreticulin. "Don't-eat-me" signals include CD47, which when expressed on the surface of a cell, inhibit phagocytosis of that cell, by activating SIRP-alpha receptors on the phagocyte. Opsonins are normally soluble proteins, which when bound to the surface of a cell induce phagocytes to phagocytose that cell. Opsonins include Mfge8, Gas6, Protein S, antibodies and complement factors C1q and C3b. [2]

Functions

Phagoptosis has multiple functions including removal and disposal of: pathogenic cells, aged cells, damaged cells, stressed cells and activated cells. Pathogenic cells such as bacteria can be opsonised by antibodies or complement factors, enabling their phagocytosis and phagoptosis by macrophages and neutrophils. "Aged" erythrocytes and neutrophils, as well as "activated" platelets, neutrophils and T-cells, are thought to be phagocytosed alive by macrophages.

Development. Phagoptosis removes excess cells during development in the worm, C. elegans. [3] [4] During mammalian development multiple cells undergo programmed cell senescence and are then phagocytosed by macrophages. [5] Brain macrophages (microglia) can regulate the number of neural precursor cells in the developing brain by phagocytosing these otherwise viable precursors and thus limiting neurogenesis. [6]

Turnover of blood cells. Red blood cells (erythrocytes) live for roughly 3 months in the blood before being phagocytosed by macrophages. Old erythrocytes do not die, but rather display changes in the cell surface that enable macrophages to recognise them as old or damaged, including exposure of phosphatidylserine, desialylation of glycoproteins, loss or changed conformation of the "don't-eat-me" signal CD47, and exposure of novel antigens that bind endogenous antibodies. [7] Neutrophils have a daily rhythm of entry and exit from the blood, driven by neutrophil “aging” in the circulation, causing decreased expression of CD62L and increased expression of CXCR4, which directs the “aged” neutrophils to the bone marrow, where they are phagocytosed by macrophages. [8] However, it is still unclear how or why neutrophils turnover at such an enormous rate. Antigen recognition causes phosphatidylserine exposure on activated T-cells, which is recognized by Tim-4 on macrophages, inducing phagoptosis of the activated T-cells, and thus the contraction phase of the adaptive response. [9]

Host defence against pathogens. Phagocytosis of otherwise-viable pathogens, such as bacteria, can be mediated by neutrophils, monocytes, macrophages, microglia and dendritic cells, and is central to host defence against pathogens. [10] Dendritic cells can phagocytose viable neutrophils, and present antigens derived from bacteria or cancer cell debris previously phagocytosed by the neutrophils. [11] Thus phagoptosis can contribute to host defence in a variety of ways.

Host defence against cancer. It has been known for some time that animals defend themselves against cancer by antibody-mediated or antibody-independent phagocytosis of viable tumour cells by macrophages. Recognition of viable cancer cells for phagocytosis may be based on the expression of novel antigens, senescence markers, phosphatidylserine or calreticulin. More recently it has become clear that most human cancer cells overexpress CD47 on their surface to prevent themselves being phagocytosed, and that if this ‘don’t-eat-me’ signalling is blocked then a variety of cancers can be cleared from the body. [12] Thus it would appear that phagoptosis is an important defence against cancer, but that tumour cells can suppress this, and blocking this suppression is an attractive therapeutic option.

Pathological phagoptosis of blood cells. Hemophagocytosis is a clinical condition, found in many infectious and inflammatory disorders, where activated macrophages have engulfed apparently viable blood cells, resulting in reduced white or red cell count (cytopenia). IFN-γ (and possibly other cytokines) appears to drive hemophagocytosis during infection by directly stimulating phagoptosis of blood cells by macrophages. [13] Hemophagocytic lymphohistiocytosis (HLH) is characterized by excessive engulfment of hematopoietic stem cells (HSCs) by bone marrow macrophages, and this has been found to result from down regulation of CD47 expression on HSCs, enabling macrophages to eat them alive. [14]

Pathological phagoptosis in the brain. Microglial phagocytosis of stressed-but-viable neurons occurs under inflammatory conditions, and may contribute to neuronal loss in brain pathologies [2].

Related Research Articles

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. The process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Phagocytosis</span> Process by which a cell uses its plasma membrane to engulf a large particle

Phagocytosis is the process by which a cell uses its plasma membrane to engulf a large particle, giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is called a phagocyte.

<span class="mw-page-title-main">Neutrophil</span> Most abundant type of granulocytes and the most abundant white blood cell

Neutrophils are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in different animals.

<span class="mw-page-title-main">Phagocyte</span> Cells that ingest harmful matter within the body

Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. They were discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.

<span class="mw-page-title-main">Microglia</span> Glial cell located throughout the brain and spinal cord

Microglia are a type of neuroglia located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS). Microglia are distributed in large non-overlapping regions throughout the CNS. Microglia are key cells in overall brain maintenance—they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium. Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. Microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed.

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.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.

<span class="mw-page-title-main">Phagosome</span>

In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).

<span class="mw-page-title-main">Antibody opsonization</span> Immune system process

Antibody opsonization is a process by which a pathogen is marked for phagocytosis.

<span class="mw-page-title-main">Innate immune system</span> One of the two main immunity strategies

The innate, or nonspecific, immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, a Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

<span class="mw-page-title-main">Alveolar macrophage</span>

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

A complement receptor is a membrane-bound receptor belonging to the complement system, which is part of the innate immune system. Complement receptors bind effector protein fragments that are produced in response to antigen-antibody complexes or damage-associated molecules. Complement receptor activation contributes to the regulation of inflammation, leukocyte extravasation, and phagocytosis; it also contributes to the adaptive immune response. Different complement receptors can participate in either the classical complement pathway, the alternative complement pathway, or both.

<span class="mw-page-title-main">C3b</span>

C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apoptotic cells for phagocytosis. Additionally, C3b plays a role in forming a C3 convertase when bound to Factor B, or a C5 convertase when bound to C4b and C2b or when an additional C3b molecule binds to the C3bBb complex.

<span class="mw-page-title-main">CD47</span> Protein-coding gene in humans

CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.

<span class="mw-page-title-main">Signal-regulatory protein alpha</span>

Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells or neurons.

A non-specific immune cell is an immune cell that responds to many antigens, not just one antigen. Non-specific immune cells function in the first line of defense against infection or injury. The innate immune system is always present at the site of infection and ready to fight the bacteria; it can also be referred to as the "natural" immune system. The cells of the innate immune system do not have specific responses and respond to each foreign invader using the same mechanism.

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.

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.

<span class="mw-page-title-main">Eat-me signals</span>

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

References

  1. ↑ Brown, Guy C.; Neher, Jonas J. (August 2012). "Eaten alive! Cell death by primary phagocytosis: 'phagoptosis'". Trends in Biochemical Sciences. 37 (8): 325–332. doi:10.1016/j.tibs.2012.05.002. PMID   22682109.
  2. 1 2 Brown, Guy C.; Neher, Jonas J. (20 March 2014). "Microglial phagocytosis of live neurons". Nature Reviews Neuroscience. 15 (4): 209–216. doi:10.1038/nrn3710. PMID   24646669. S2CID   679487.
  3. ↑ Hoeppner, D.J. et al (2001). Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202-206
  4. ↑ Reddien, P. et al (2001). Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198-202
  5. ↑ Muñoz-Espín D et al Programmed cell senescence during mammalian embryonic development. Cell. 2013;155:1104-18.
  6. ↑ Cunningham, C. L., Martinez-Cerdeno, V. & Noctor, S. C. Microglia Regulate the Number of Neural Precursor Cells in the Developing Cerebral Cortex. Journal of Neuroscience 33, 4216–4233 (2013).
  7. ↑ Lutz HU, Bogdanova A. Mechanisms tagging senescent red blood cells for clearance in healthy humans. Front Physiol. 2013;4:387
  8. ↑ Casanova-Acebes M, et al. Rhythmic Modulation of the Hematopoietic Niche through Neutrophil Clearance. Cell. 2013;153:1025-35.
  9. ↑ Albacker, L.A. et al (2010) TIM-4, a receptor for phosphatidylserine, controls adaptive immunity by regulating the removal of antigen-specific T cells. J Immunol. 185, 6839-49
  10. ↑ Lovewell RR, Patankar YR, Berwin B. Mechanisms of phagocytosis and host clearance of Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol. 2014 306:L591-603. Mayadas TN, Cullere X, Lowell CA. The multifaceted functions of neutrophils. Annu Rev Pathol. 2014;9:181-218.
  11. ↑ Alfaro C et al. Dendritic cells take up and present antigens from viable and apoptotic polymorphonuclear leukocytes. PLoS One. 2011;6:e29300.
  12. ↑ Chao MP, Majeti R, Weissman IL. Programmed cell removal: a new obstacle in the road to developing cancer. Nat Rev Cancer. 2011 Dec 8;12(1):58-67.
  13. ↑ Zoller, E.E. et al (2011) Hemophagocytosis causes a consumptive anemia of inflammation. J Exp Med. 208, 1203-14
  14. ↑ Kuriyama T et al (2012) Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis. Blood 120:4058-67.
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