However, during monocyte-to-macrophage differentiation the enzymes PI 3-K and ERK are recruited in an orderly fashion for efficient phagocytosis Similarly, PLA2 is also implicated in regulation of phagocytosis. During phagocytosis, various PLA2 isoforms participate in releasing arachidonic acid from membrane triglyceride lipids.
Thus, during monocyte-to-macrophage differentiation important signaling enzymes are reorganized in order to achieve enhanced phagocytosis. Phagocytosis is a fundamental process for the ingestion and elimination of microbial pathogens and apoptotic cells. All types of cells can perform phagocytosis, but specialized cells called professional phagocytes do it much more efficiently. Phagocytosis is vital, not only for eliminating microbial pathogens, but also for tissue homeostasis.
Because there are different types of phagocytic cells and they can ingest a vast number of different targets, it is evident that phagocytosis involves diverse mechanisms.
For other phagocytic receptors, we are just beginning to describe the signaling pathways they use to activate phagocytosis. Today, we have a better understanding on the process of phagosome maturation, but there are still many gaps in our knowledge of the signaling pathways regulating this process. Similarly, the resolution of the phagolysosome, after degradation of the ingested particle, is a topic that requires further research. Many important questions remain unsolved. For example, how different phagocytic receptors on the same cell work together?
An improved understanding of phagocytosis is essential for future therapeutics related to infections and inflammation. EU-Q prepared the reference list, made the figures and reviewed the manuscript.
CR conceived the issues which formed the content of the manuscript and wrote the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Rabinovitch M. Professional and non-professional phagocytes: an introduction. Trends Cell Biol.
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Bezman N, Koretzky GA. The phagocytes grouped in the MYPS include the leukocytes neutrophils, inflammatory monocytes, macrophages, and immature myeloid DCs. Here the justifications behind the inclusion of neutrophils in a phagocyte system is expanded and the MYPS are further characterized as a group of dedicated phagocytic cells that function in an interacting and cooperative way in the host defense against microbial infection.
Neutrophils and macrophages are considered the main arms of this system. When infectious agents pass the peripheral defenses and invade sterile body territories they face innate antimicrobial mechanisms. The pathological result of the presence of a microbe within a host is dependent on the virulence of the pathogen and on the defense competence of the host Finlay and Falkow, ; Casadevall and Pirofski, When functioning as a pathogen, the infectious agent is living from its pathogenicity, but when the host antimicrobial protective mechanisms dominate there is the efficient protective intervention of several immune and non-immune cells.
This intervention is crucially centered on the antimicrobial activities of phagocyte cells, mainly macrophages and neutrophils. Although epithelial cells, fibroblasts, and other cells can phagocytose, in this text the term phagocytes is used for cells whose main function is phagocytosis and that have been classically called professional or dedicated phagocytes, namely neutrophils, inflammatory monocytes, macrophages, and immature dendritic cells DCs.
Although phagocytes operate using phagocytic and non-phagocytic mechanisms Silva, a , b , phagocytosis is the activity that confers their typical character. While lower eukaryotes use phagocytosis mainly for the acquisition of nutrients, phagocytosis in metazoans is primarily carried out by the specialized professional phagocytes, macrophages, and neutrophils, for a wide range of tasks that include, but are not restricted to, uptake and destruction of invading pathogens Dale et al.
His seminal observations behind the phagocytosis theory are extensively discussed in two publications translated to English Metchnikoff, , and in biographic texts see for example Tauber, ; Kaufmann, Metchnikoff understood that phagocytosis represents a central defense mechanism of the host against microbial invaders. The main roots of the theory of phagocytic cells originated from the initial observations made in starfish larva and later in vertebrates.
In , working with natural yeast infection in Daphnia, he reported on the antimicrobial activity of phagocytes. In spite of the importance Metchnikoff attributed to neutrophils as a phagocyte archetype, the post-Metchnikoff evolving trend was to consider macrophages the essential phagocytes minimizing the importance of neutrophils.
This cell was considered at the time a terminally differentiated phagocyte with very limited functional capacities.
However, the evolution of knowledge about phagocytes progressively led to a new concept of neutrophils as archetypical phagocytic and modulator immune cells, with an origin common to that of the macrophages Cassatella, , ; Rabinovitch, ; Akashi et al. This new perspective of the neutrophil highlighted novel unexpected capabilities for this essential component of the immune system, which is still under further study nowadays.
Although varying among mammals, the antimicrobial capacity of neutrophils is higher than that of macrophages Levy, ; Segal, Neutrophils are equipped with a huge assortment of microbicidal mechanisms and use multiple antimicrobial molecules stored in enormous amounts in granules Borregaard and Cowland, ; Segal, Production of ROS is most prominent in neutrophils as compared with macrophages Nathan and Shiloh, Several antimicrobial proteins that are an important part of the neutrophil arsenal are lacking or scarce in the tissue macrophage Levay and Viljoen, ; Lehrer and Ganz, ; Selsted and Ouellette, This is the case of defensins and cathelicidins, the major families of mammalian antimicrobial peptides of neutrophils Ganz, , and of lactoferrin Levay and Viljoen, Myeloperoxidase MPO , which is an important enzyme involved in oxidative antimicrobial mechanisms of neutrophils, is present in circulating mammal monocytes but is lost as these mature into macrophages Klebanoff, , which correlates with decay in antimicrobial activity Locksley et al.
Biological cellular systems are groups of cells that share common features, mostly function and origin Aschoff, ; van Furth et al. Following the pioneer studies by Metchnikoff several systems of phagocytic cells have been created and, strangely, all these were confined to mononuclear cells and excluded neutrophils. One argument used in the proposal of these mononuclear systems was that Metchnikoff considered macrophages as the major phagocytic cells, an interpretation that, as discussed above, is not justified.
This proposal was formally published van Furth et al. When the MPS was proposed, knowledge on myelogenesis was limited and the common origin of neutrophils and macrophages was not known, the neutrophils being considered to belong to a cell line separated from that of the MPS members and to be a terminally differentiated phagocytic effector with limited kinetic and functional capacities.
Comprehensive phagocyte cell systems must include neutrophils and Silva recently proposed an enlarged system grouping dedicated phagocytic cells including neutrophils Silva, a. Here the justifications for such proposal are extended and the MYPS are further characterized focusing on human and mouse studies.
Main steps and players of myelopoiesis in the context of the MYPS. Graph depicting one interpretation of the still evolving view of the myelopoiesis pathways blue arrows associated with the poiesis of the members of the MYPS in mice and humans. This interpretation takes into consideration recent publications whose references are given below see also the reviews Friedman, ; Iwasaki and Akashi, ; Varol et al. Monocytes mature into Macrophages 6 van Furth et al. The members of the MYPS are highlighted in bold.
The leukocytes of the MYPS share origin, avid phagocytic abilities, and kinetics. Regarding their morphology, the precursor forms of all members of the MYPS are similar except for the mature circulating neutrophil.
Mature neutrophils are mononuclear like the other members of the MYPS but the terminal mature form is morphologically differentiated and has a polylobed nucleus. The list of MYPS members proposed below may have to be altered according to the continuously evolving knowledge in this area. This is particularly relevant for DCs since they share to a great extent the origin and function of other cell members of the MYPS.
Of notice, all except neutrophils are antigen-presenting cells. However, since the concept of MYPS, as it stands presently, requires a high phagocytic profile, among the DC cell populations, only immature myeloid DCs were included. All granulocytes are phagocytic but neutrophils mouse and human key markers: CD66b, LY6-G are the only exhibiting avid phagocytosis.
As already stressed, neutrophils have been acquiring a progressive status of fundamental phagocytic immune cells Cassatella, , ; Rabinovitch, ; Cassatella et al. Comprehensive reviews on these leukocytes include recent contributions Nathan, ; Nauseef, ; Dale et al. Inflammatory monocytes are phagocytic and use this capacity as an antimicrobial mechanism Grage-Griebenow et al.
Many recent comprehensive reviews on these phagocytes are available Hume, ; Mosser and Edwards, ; Serbina et al. They are a group of primarily antigen presenting and immunomodulatory cells whose distinctiveness has been debated Hume, ; Geissmann et al.
Mature DCs are not considered dedicated phagocytes and have not been included in the group of professional phagocytes Rabinovitch, Mature DCs have a limited capacity for lysosomal degradation of ingested material Delamarre et al.
On the other hand, immature myeloid DCs are phagocytic Inaba et al. Thus, they are included as members of the MYPS. Several arguments justify the inclusion of neutrophils in any comprehensive phagocyte cell system, as follows. Macrophages and neutrophils share important features: Important features shared by macrophages and neutrophils with respect to their common origin include: i avid phagocytic capabilities Dale et al.
Also to consider are reports on the possible conversion of neutrophils into macrophages Araki et al. Additionally, two functional criteria that were taken into consideration to select cells to be grouped in the MPS, namely pinocytosis and the ability to attach firmly to a glass surface van Furth et al. Data discussed above and elsewhere Silva, a , b , indicate that the MYPS is an assembly of dedicated phagocytic cells that function in an interacting and cooperative way.
While sharing several functions, macrophages and neutrophils are specialized cells with functional and function-related morphological distinctive features. These features are complementary and provide varied levels of antimicrobial capacities and cytotoxicity, and tissue-specific localization and lifespan Silva, a. These distinctive features explain why macrophages and neutrophils are not able to replace each other as central players of antimicrobial immunity, as indicated by the pathology associated with some human and murine phagocyte deficiencies Dale and Liles, The combination of shared and complementary features of macrophages and neutrophils promotes their cooperative participation as effectors and modulators in immunity against infection Silva, a , b.
This cooperation is clearly illustrated by the ability of macrophages, in their process of killing intracellular bacteria, to take up proteins and peptides e. In addition, macrophages are also able to engulf apoptotic neutrophils and make use of the antimicrobial molecules present in their granules.
Based on these results Silva et al. In situations where macrophages handle diverse intramacrophage microbes in different ways, antimicrobial components of neutrophil granules, acquired by macrophages through uptake of neutrophils or neutrophil granules, are mobilized to the diverse types of microbe-containing vacuoles Silva, At these locations the acquired molecules may exert their antimicrobial role through a direct activity against the intramacrophage pathogens Sharma et al.
A similar concept was proposed after the initial paper by Silva Soehnlein and Lindbom, This cooperative partnership represents a factor for increased efficiency of the MYPS. As already noted by Metchnikoff , the presence of two professional phagocytes is exclusive of the immune system of vertebrates. This is a safe way of macrophages to make use of powerful but dangerous microbicidal molecules avoiding the problems of permanently carrying these cytotoxic factors.
This strategy is a target of key virulence mechanisms of successful pathogens. Based on the principle that phagocyte cell systems must include all dedicated phagocytic cells, the creation of the MYPS Silva, a was proposed, changing the unacceptable prevailing situation where the only phagocyte cell system in use MPS excludes neutrophils.
The members of this system have common origin and share avid phagocytic abilities. Thus, neutrophils and macrophages are the main arms of this system. In conclusion, the MYPS is a system of dedicated phagocytic cells that groups neutrophils, inflammatory monocytes, macrophages, and immature myeloid DCs; these functions in an interacting and cooperative way in the host defense against microbial infection.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Akashi, K. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature , — Araki, H. Reprogramming of human postmitotic neutrophils into macrophages by growth factors. Blood , — Aschoff, L. NY: Paul B. Hoeber, Inc. Banchereau, J. Immunobiology of dendritic cells. Dendritic cells and the control of immunity.
Borregaard, N. This study examined the degree of spirochete clearance likely to occur with PMNL or mononuclear cells before the development of the secondary immune response.
Without specific antibody in vitro, there was very limited uptake of spirochetes by PMNL or monocytes and no intracellular colocalization of PMNL granule products with spirochetes. Most of the killing of spirochetes by PMNL was extracellular.
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