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Structural aspects of the endosome-lysosome system involved in intracellular digestion. a Schematic diagram of phagocyte with its intracellular membrane-bound compartments. Left side of diagram shows the endosomal-lysosomal pathway (thick gray hatched line) that degrades small food particles absorbed by pinocytosis. Compartments are identified by terms generally used in current textbooks and research literature. Right side of diagram depicts the phagosome-lysosome pathway followed by large food particles ingested by phagocytosis. Electron micrographs (b-b″″′, c′-c″, d, e) illustrate shape and texture of compartments shown in
Source publication
The uptake of macromolecules and larger energy-rich particles into the cell is known as phagocytosis. Phagocytosed material is enzymatically degraded in membrane-bound vesicles of the endosome/lysosome system (intracellular digestion). Whereas most, if not all, cells of the animal body are equipped with the molecular apparatus for phagocytosis and...
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... uptake of material into the cell, termed endocytosis, follows three different pathways, (micro)pinocytosis, phagocytosis, and macropinocytosis ( Pollard et al. 2017; Fig. 2a-b′). Fluids and particles measuring less than 0.5 μm are taken up by pinocytosis; the ingestion of larger particles occurs by phagocytosis or macropinocytosis. In pinocytosis, the membrane buckles inward in the shape of a small invagination ("pit"). Several different invagination mechanisms, notably clathrin-dependent endocytosis, ...
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... ("pit"). Several different invagination mechanisms, notably clathrin-dependent endocytosis, caveolin-dependent endocytosis, and clathrin/caveolin independent endocytosis, have been distinguished thus far (Mayor and Pagano 2007). Endocytotic pits pinch off the membrane to form the primary endocytotic vesicles, which measure 0.1-0.2 μm in diameter (Fig. 2a, b″). By contrast, in phagocytosis, microfilamentdriven lamellipodia extend outward around the large particle ("cargo"; e.g., bacterium, cell, cell fragment) that is to be ingested ( Rougerie et al. 2013). This process is orchestrated by the interactions between cargo surface molecules and receptors on the phagocyte which then recruit ...
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... fluid, with or without particulate matter. As opposed to phagocytosis, macropinocytosis does not depend on specific ligand-receptor interactions. The vesicles resulting from phagocytosis and macropinocytosis are larger than the primary endocytotic vesicles that follow (micro)pinocytosis and are termed phagosomes and macropinosomes, respectively (Fig. ...
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... dock at the early endosomes (EE), an elaborate network of interconnected vesicles and tubules located close to the plasma membrane (Huotari and Helenius 2011;Repnik et al. 2013;Pollard et al. 2017;Fig. 2a). From here, certain parts of the internalized membrane are continuously recycled outward to the plasma membrane via recycling endosomes (Fig. 2a). At the same time, vesicles carrying digestive enzymes and diverse membrane proteins arrive from the trans-Golgi network and merge with the EEs. As a result, large pieces of the EE vesicular network break off and are transported towards more central positions within the cytoplasm via microtubular transport ( Bonifacino and Neefjes ...
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... ( Bonifacino and Neefjes 2017). These so-called carrier vesicles, aside from containing endocytosed food material and digestive enzymes, are characterized structurally by having many small internal vesicles enclosed within their lumen and are therefore called multivesicular bodies ( Gruenberg and Stenmark 2004;Pollard et al. 2017; MVBs in Fig. 2a, b″′). MVBs become part of another vesicular network, the late endosome (LE). Like EEs, LEs continuously exchange membrane-bound and intraluminal proteins with the trans-Golgi network. They differ from EEs by a number of specific membrane-bound proteins, such as the GTPase Rab7, which marks LEs, as opposed to Rab5, which is characteristic ...
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... LE system interacts with yet another vesicular intracellular compartment, the lysosome. Lysosomes are round or irregularly shaped vesicles of 0.1-1 μm diameter, filled with a homogenous, moderately electron-dense interior surrounded by a narrow, light halo (De Duve and Wattiaux 1966;Huotari and Helenius 2011; Lim and Zoncu 2016; Fig. 2a, b″″). Lysosomes contain digestive enzymes, like acid phosphatase, and form part of all cells but occur at greater density in cells that, like macrophages or hepatocytes, digest and store food materials. The fusion of lysosomes and LEs yields a hybrid vesicle, the endolysosome. This organelle, also called "secondary lysosome," is ...
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... The fusion of lysosomes and LEs yields a hybrid vesicle, the endolysosome. This organelle, also called "secondary lysosome," is characterized by its heterogenous content that consists of electron-dense droplets of varying size and shape, as well as membranous vesicles and lamellar structures (Huotari and Helenius 2011;Pollard et al. 2017; Fig. 2a, b″″′). Like all other components of the endosome/lysosome system, endolysosomes also appear to be dynamic structures that undergo constant fusion-fission events. Parts of their membranes and enzymatic content get removed to reform lysosomes; vesicles derived from the trans-Golgi network carrying cargoes of "fresh" enzymes and membrane ...
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... appearance of EE, MVB, LE and endolysosome appears to be very different depending on the size of the initially endocytosed volume. Primary endocytic vesicles generated through pinocytotic membrane invaginations are similar in size to the vesicular structures of "typical" EEs, MVBs, and LEs documented in the literature (Huotari and Helenius 2011; Fig. 2b″, b″′). By contrast, phagosomes and macropinosomes (1-5 μm) "dwarf" endocytic vesicles (Hard 1972;Buchmeier and Heffron 1991;Tjelle et al. 2000;Haas 2007;Kinchen and Ravichandran 2008; Fig. 2a-c′). Once moving deeper into the cell, phagosomes remain large, rather than breaking down into smaller vesicles. Most ultrastructural descriptions of ...
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... invaginations are similar in size to the vesicular structures of "typical" EEs, MVBs, and LEs documented in the literature (Huotari and Helenius 2011; Fig. 2b″, b″′). By contrast, phagosomes and macropinosomes (1-5 μm) "dwarf" endocytic vesicles (Hard 1972;Buchmeier and Heffron 1991;Tjelle et al. 2000;Haas 2007;Kinchen and Ravichandran 2008; Fig. 2a-c′). Once moving deeper into the cell, phagosomes remain large, rather than breaking down into smaller vesicles. Most ultrastructural descriptions of phagocytosis imply that phagosomes directly fuse with lysosomes into phagolysosomes (e.g., Kinchen and Ravichandran 2008). Intermediate carrier vesicles resulting from the processing of ...
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... off from the endoplasmic reticulum, LBs are round, electrondense vesicles surrounded by a specialized membrane that is formed by a lipid monolayer (Murphy 2001;Melo et al. 2011). In fixation protocols for electron microscopy lipids are often dissolved, leaving "empty spaces" of characteristic size, shape, and distribution instead of the dense LBs (Fig. ...
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... telolysosomes, which resemble phagolysosomes to a certain extent. Residual bodies also contain highly polymorphic granular and membranous material ("myelin figures"), but are typically smaller, more irregularly shaped, and higher in electron density than phagolysosomes ( Fedorko et al. 1968;Novikoff 1973;Essner and Haimes 1977;Del Conte 1979; Fig. 2a, e). Residual bodies can accumulate in the cytoplasm as "lipofuscin granules" or can be expelled from the cell by exocytosis ( Kajihara et al. 1975;Hendriks and Eestermans ...
Citations
... After exposure of the digestive or respiratory system, only a small amount of smaller microplastics is translocated to internal tissues (< 1%) [122,124] . Some microplastics will find their way into the blood and become systemically distributed until they get caught into narrow capillary beds (e.g., < 5 µm in human lungs) [125] or are removed by the macrophages of the reticuloendothelial system [126] . Microplastics are then eliminated into the bile or the gastrointestinal lumen, where they will be excreted in the feces [127] . ...
Microplastics are environmental contaminants consisting of small plastics ≤ 5 mm. Concerns over the adverse effects of microplastics have led to a rapid growth in the available literature despite the lack of harmonized methods and materials. Therefore, the field is becoming increasingly daunting to new researchers. A state-of-the-art guide was assembled following a comprehensive literature review of microplastics research with the intent of addressing contemporary challenges, prioritized based on a survey, and introducing best practices. The lack of standardized methods and reference materials, the lack of access to analytical equipment, and the difficulty in working with lower environmental concentrations in laboratory tests (e.g., toxicity assays) remain a great challenge. The present work addresses these issues across three main sections: definitions, sampling, and evaluation of adverse effects. Harmonized methods and greater collaboration were identified as opportunities in this rapidly evolving field. A review of available interlaboratory comparison tests was also conducted to support additional recommendations.
... In my view, both observations, namely amoeboid cells in the mesoglea and phagocytic cells in the primitive gut, are a reflection of immunity (protection) and survival (nutrition) behaviors. (Hartenstein and Martinez, 2019). As will be discussed later, immunity (protection) arose from the epithelial-mesenchymal transition (EMT) of the primitive intestine ( Figure 1B), constituting the neoplastic basis for the formation of the first embryo. ...
... The first resources of our first embryo likely stemmed from multiflagellate fusion and were therefore scarce until the formation of the primitive gut (Presnell et al., 2016). It is easy to understand why TLRs (PRRs in general) are so strongly related to embryology (dorsal/ventral patterning was their first function) (Lemaitre et al., 1996), cancer (immunotherapy) (Anderson, 2000;Chen et al., 2008;Rakoff-Nahoum and Medzhitov, 2009;So and Ouchi, 2010;Pradere et al., 2014;Shi et al., 2016;Braunstein et al., 2018), and the survival of the first animal (enteric phagocytosis) (Hartenstein and Martinez, 2019). ...
The formation of the innate immune system of animals can only be envisioned after the development of the first metazoan embryo. The decisive role of Embryology in understanding the evolution of the immune system has been inexplicably disregarded in the history of science. Some characteristics of our holozoan ancestors, including macrophage-like movement and enteric phagocytosis, were suppressed by the formation of chains of physically attached cells in the context of embryo multicellularity. The formation of the archenteron during morphogenesis of the first embryo resulted in a meta-organism whose survival was dependent on the ability to perform enteric phagocytosis (nutrition on bacteria). By recognizing the neoplastic basis of embryo formation, it is possible to venture a glimpse at its other face, a process that becomes evident when the extracellular matrix and cadherin junctions are destroyed. What ensues is metastasis (in the case of cancer) or an alternative version controlled by cell differentiation (during embryogenesis). In the context of innate immunity, the development of mesogleal cells by epithelial–mesenchymal transition and differentiation into cells specialized in bacterial recognition allowed the newly formed animal to preserve homeostasis, an innovation that has been maintained throughout evolution. In this article, I will share my first reflections on the embryonic origin of innate immunity and its close relationship with cancer. Innate immunity arises naturally during embryogenesis, which explains why the immune system typically does not react against cancer cells. In its essence, the immune system was created from them. Here, I argue that the first embryo can be understood as a benign tumor nourished and protected by the innate immune system.
... Phagocytes can be free-living single-celled organisms, such as ciliates, or body cells such as neutrophils in peripheral blood. In some ciliates, phagocytosis acts as a feeding mechanism, while in higher eukaryotes it primarily serves as a defensive response against invasion by antigens (Allen and Fok 2000;Hartenstein and Martinez 2019). ...
Exogenous RNA poses a continuous threat to genome stability and integrity across various organisms. Accumulating evidence reveals complex mechanisms underlying the cellular response to exogenous RNA, including endo-lysosomal degradation, RNA-dependent repression and innate immune clearance. Across a variety of mechanisms, the natural anti-sense RNA-dependent defensive strategy has been utilized both as a powerful gene manipulation tool and gene therapy strategy named RNA-interference (RNAi). To optimize the efficiency of RNAi silencing, a comprehensive understanding of the whole life cycle of exogenous RNA, from cellular entry to its decay, is vital. In this paper, we review recent progress in comprehending the recognition and elimination of foreign RNA by cells, focusing on cellular entrance, intracellular transportation, and immune-inflammatory responses. By leveraging these insights, we highlight the potential implications of these insights for advancing RNA interference efficiency, underscore the need for future studies to elucidate the pathways and fates of various exogenous RNA forms, and provide foundational information for more efficient RNA delivery methods in both genetic manipulation and therapy in different organisms.
... Phagocytosis is a fundamental cell behavior central to many metazoan cell processes, including nutrient uptake and immune response (Hartenstein and Martinez, 2019). Cells competent for phagocytosis can be readily identified using FACS by selecting cells that have internalized fluorescent particles (Lehmann et al., 2000). ...
Cell suspension fluidics, such as flow cytometry (FCS) and fluorescence-activated cell sorting (FACS), facilitates the identification and precise separation of individual cells based on phenotype. Since its introduction, flow cytometry has been used to analyze cell types and cellular processes in diverse non-vertebrate taxa, including cnidarians, molluscs, and arthropods. Ctenophores, which diverged very early from the metazoan stem lineage, have emerged as an informative clade for the study of metazoan cell type evolution. We present standardized methodologies for flow cytometry-mediated identification and analyses of cells from the model ctenophore Mnemiopsis leidyi that can also be applied to isolate targeted cell populations. Here we focus on the identification and isolation of ctenophore phagocytes. Implementing flow cytometry methods in ctenophores allows for fine scale analyses of fundamental cellular processes conserved broadly across animals, as well as potentially revealing novel cellular phenotypes and behaviors restricted to the ctenophore lineage.
... These small molecules are then transported on the brush border membrane into enterocytes by specific transporters, e.g., monosaccharide transporters SGLT1 and GLUT5, the peptide transporter PEPT1, and the amino acid transporter B 0 AT1 (Burant et al. 1992;Leibach and Ganapathy 1996;Bröer et al. 2004;Gorboulev et al. 2012; also refer to Table 1 for full gene names). Pinocytosis and phagocytosis in vertebrates are also associated with nutrient uptake using endocytosis-associated molecules, e.g., cell surface receptors LRP2/ megalin, cubilin, amnionless, and MRC1, the cell surface adapter Dab2, the late endosome protein Rab7, lysosomal membrane protein LAMP, and lysosomal proteases cathepsins (Novinec and Lenarčič 2013;Vázquez-Carretero et al. 2014;Wang et al. 2018;Hartenstein and Martinez 2019b;Park et al. 2019; also refer to Table 1 for full gene names). During the processing of nutrients, enterocytes and other types of intestinal cells protect the alimentary epithelium from pathogens by secreting mucus and inducing immune responses (Chassaing et al. 2014;Johansson and Hansson 2016). ...
... Pinocytosis-and/or phagocytosis-related proteins play a role in epithelial absorption in the animal alimentary canal (Hartenstein and Martinez 2019b;Park et al. 2019). To examine pinocytosis-/phagocytosis-related GEP in the ascidian, WISH was performed using Ciona juveniles and the dissected post-pharyngeal tract of young adults. ...
... Intestinal absorption-related functions, not only absorption, but also pinocytosis and phagocytosis, are important for heterotrophic bilaterians to take up nutrients from the surface of the intestinal epithelium (Hartenstein and Martinez 2019b). Although chordates share a fundamental body plan and molecular background (Satoh 2016), their intestinal structures, associated molecules, and gene usage are highly divergent. ...
Intestinal absorption is essential for heterotrophic bilaterians with a tubular gut. Although the fundamental features of the digestive system were shared among chordates with evolution, the gut morphologies of vertebrates diverged and adapted to different food habitats. The ascidian Ciona intestinalis type A, a genome-wide research model of basal chordates, is used to examine the functional morphology of the intestines because of its transparent juvenile body. In the present study, the characteristic gene expression patterns (GEP) of Ciona absorptive proteins, e.g., brush border membrane enzymes for terminal digestion (lactase, maltase, APA, and APN) and transporters (SGLT1, GLUT5, PEPT1, and B0AT1), were investigated in juveniles and young adults, with a special reference to the absorption of other nutrients by pinocytosis- and phagocytosis-related proteins (megalin, cubilin, amnionless, Dab2, Rab7, LAMP, cathepsins, and MRC1). Whole-mount in situ hybridization revealed that these GEP showed multi-regional and repetitive features along the Ciona gastrointestinal tract, mainly in the stomach and several regions of the intestines. In young adults, many absorption-related genes, including pinocytosis-/phagocytosis-related genes, were also expressed between the stomach and mid-intestine. In the gastrointestinal epithelium, absorption-related genes showed zonal GEP along the epithelial structure. Comparisons of GEP, including other intestinal functions, such as nutrient digestion and intestinal protection, indicated the repetitive assignment of a well-coordinated set of intestinal GEP in the Ciona gastrointestinal tract.
... Therefore, "ceroid" was used in this study to refer to the pigmented granules. Ceroid-lipofuscin accumulation has been considered to be an outcome of inadequate intra-lysosomal digestion from the phagocytosis process, these residual granules accumulate in the cell's cytoplasm, which can then be expelled into the connective tissue (Hendriks and Eestermans, 1986;Basova et al., 2012;Hartenstein and Martinez, 2019). In addition, accumulation may also indicate previous and ongoing pathological conditions i.e., APX and Perkinsus sp. ...
... This process was then followed by parasite-mediated inhibition once infection was established, with Perkinsus cells developing into replicative trophozoites. Partial phagocytosing could have resulted in the inadequate intra-lysosomal digestion and therefore further accumulation of ceroid material as described in the above section (Hendriks and Eestermans, 1986;Hartenstein and Martinez, 2019). ...
... Phagocytosis includes the recognition and ingestion of particles larger than 0.5 µm within a plasma-membrane envelope (i.e., phagosome) (Rosales and Uribe-Querol, 2017). It is a highly conserved cellular process from unicellular to multicellular organisms, involved in nutrition, defense, homeostasis and symbiosis (Nyholm and Graf, 2012;Lim et al., 2017;Hartenstein and Martinez, 2019). Symbionts from diverse hosts such as amoeba, leech and squid are capable of escaping different stages of the phagocytic process, avoiding either incorporation or digestion by host cells (e.g., Silver et al., 2007;Nyholm et al., 2009;Nguyen et al., 2014), in their way to colonize and persist in the animal host. ...
Introduction
Sponges harbor diverse, specific, and stable microbial communities, but at the same time, they efficiently feed on microbes from the surrounding water column. This filter-feeding lifestyle poses the need to distinguish between three categories of bacteria: food to digest, symbionts to incorporate, and pathogens to eliminate. How sponges discriminate between these categories is still largely unknown. Phagocytosis is conceivable as the cellular mechanism taking part in such discrimination, but experimental evidence is missing. We developed a quantitative in-vivo phagocytosis assay using an emerging experimental model, the sponge Halichondria panicea.
Methods
We incubated whole sponge individuals with different particles, recovered the sponge (host) cells, and tracked the incorporation of these particles into the sponge cells. Fluorescence-activated cell sorting (FACS) and fluorescent microscopy were used to quantify and verify phagocytic activity, defined here as the population of sponge cells with incorporated particles. Sponges were incubated with a green microalgae to test if particle concentration in the seawater affects the percentage of phagocytic activity, and to determine the timing where the maximum of phagocytic cells are captured in a pulse-chase experiment. Lastly, we investigated the application of our phagocytic assay with other particle types (i.e., fluorescently-labelled bacteria and fluorescent beads).
Results and discussion
The percentage of sponge cells that had incorporated algae, bacteria, and beads ranged between 5 to 24%. These phagocytic sponge cells exhibited different morphologies and sizes depending on the type of particle presented to the sponge. Particle incorporation into sponge cells was positively related to algal concentration in the seawater, suggesting that sponge cells adjust their phagocytic activity depending on the number of particles they encounter. Our results further revealed that sponge phagocytosis initiates within minutes after exposure to the particles. Fluorescent and TEM microscopy rectified algal internalization and potential digestion in sponge cells. To our knowledge, this is the first quantitative in-vivo phagocytosis assay established in sponges that could be used to further explore phagocytosis as a cellular mechanism for sponges to differentiate between different microorganisms.
... Similarly, no evidence for accumulation in the human body has so far been described, to the best of the author's knowledge. Clearance of preserved particles mainly occurs through the phagocytes of the reticuloendothelial system, primarily by Kupffer cells in the liver and to a lesser extent by macrophages in the spleen and bone marrow (Hartenstein & Martinez, 2019;, in liver endothelial cells and hepatocytes followed by exocytosis in the bile (Handy et al., 2008;, or trapping in the splenic interendothelial cell-slits (Moghimi et al., 1991). Kupffer cells play an important role in the phagocytosis of synthetic particles, including of larger sizes, removing 60 -70% of 50 and 500 nm of polystyrene after intravenous administration in rats . ...
Microplastics are widespread contaminants leading to environmental exposure. While studies on the prevalence in human tissues have multiplied, little is known about their pharmacokinetics. Mechanisms of absorption, distribution, metabolism, and excretion (ADME) must be addressed before effects on human health (i.e. pharmacodynamics) can be understood. Therefore, the objective of this review was to provide an integrated assessment on the fate of microplastics in the human body by gathering information from multiple fields of research (e.g. implants and microspheres). Absorption of microplastics mainly occurs through transcytosis in enterocytes, while larger particles may be internalized through gaps (e.g. persorption) or by uptake by phagocytes. Only microplastics <5 µm may reach the alveolar region, while large particles found in the lungs usually result from entrapment of circulating particles in the narrow pulmonary capillary network. Overall, absorption rates of microplastics are expected to be low. Microplastics are then distributed by the circulatory system, accumulating in the respiratory system, digestive system, liver, spleen, and brain. Metabolism may lead to the biodegradation of microplastics, mainly through enzymes and reactive oxygen species of macrophages, exposure to physiologic fluids, and microbiologic activity in the gut lumen. Finally, most microplastics will be removed by the liver or spleen and excreted in the feces. While this work provides an initial attempt at constructing a pharmacokinetics model for microplastics, further research is required. Ideally, future works should be conducted using histopathology techniques to obtain the precise location in the tissues and radiolabelled particles to allow tracking through time.
... We speculate that many of these genes are analogous to those characteristically used by macrophages to carry out similar functions. Given that most of the characteristic features of macrophages observed in Acanthamoeba are associated with bacterial recognition, endocytosis, and elimination, we hypothesize that these abilities later evolved into a protective bactericidal function as part of the host immune response in multicellular animals (Hartenstein and Martinez, 2019). This suggests that the evolutionary origin of the bactericidal function of mammalian macrophages arose prior to the branching of Amoebozoa and Opisthokonta, most likely in the environment of a free-living unicellular amoeboid cell. ...
... Nutrients must then be distributed throughout the body, from choanocytes to other cell types. This function is performed by archaeocytes, which receive nutrients from choanocytes and transport them, by virtue of their high motility, throughout the mesophyll to the nutritionally demanding cells (Hartenstein and Martinez, 2019). ...
... Since archaeocytes are freely motile and play a protective role in sponges, they show functional similarities to macrophages of bilaterians, therefore, it is feasible that archaeocytes represent the ancestors of these cells. The mechanism of nutrient uptake by choanocyte-like cells and nutrient distribution by freely motile amoebocytes is highly conserved in animals, with the exception of vertebrates and insects (Hartenstein and Martinez, 2019). ...
Macrophages represent the most functionally versatile cells in the animal body. In addition to recognizing and destroying pathogens, macrophages remove senescent and exhausted cells, promote wound healing, and govern tissue and metabolic homeostasis. In addition, many specialized populations of tissue-resident macrophages exhibit highly specialized functions essential for the function of specific organs. Sometimes, however, macrophages cease to perform their protective function and their seemingly incomprehensible response to certain stimuli leads to pathology. In this study, we address the question of the origin of the functional versatility of macrophages. To this end, we have searched for the evolutionary origin of macrophages themselves and for the emergence of their characteristic properties. We hypothesize that many of the characteristic features of proinflammatory macrophages evolved in the unicellular ancestors of animals, and that the functional repertoire of macrophage-like amoebocytes further expanded with the evolution of multicellularity and the increasing complexity of tissues and organ systems. We suggest that the entire repertoire of macrophage functions evolved by repurposing and diversification of basic functions that evolved early in the evolution of metazoans under conditions barely comparable to that in tissues of multicellular organisms. We believe that by applying this perspective, we may find an explanation for the otherwise counterintuitive behavior of macrophages in many human pathologies.
... Cnidarian gastrodermis, flatworm phagocytes and nematode pseudocoelomocytes reveal similarity to vertebrate immune cells to form a dense 'immune' clade, thus suggesting common origin of immunity and digestion (Hartenstein & Martinez, 2019). This evidence fully recapitulates the classical Metchnikoff's phagocytic RUSIN | 5 of 20 theory of immunity, where he posited that the roots of cellular immunity lie in the common origin of macrophages and gastric cells of lower metazoans (Metchnikoff, 1901;Metschnikoff, 1884). ...
The concept of homology lies in the heart of comparative biological science. The distinction between homology as structure and analogy as function has shaped the evolutionary paradigm for a century and formed the axis of comparative anatomy and embryology, which accept the identity of structure as a ground measure of relatedness. The advent of single‐cell genomics overturned the classical view of cell homology by establishing a backbone regulatory identity of cell types, the basic biological units bridging the molecular and phenotypic dimensions, to reveal that the cell is the most flexible unit of living matter and that many approaches of classical biology need to be revised to understand evolution and diversity at the cellular level. The emerging theory of cell types explicitly decouples cell identity from phenotype, essentially allowing for the divergence of evolutionarily related morphotypes beyond recognition, as well as it decouples ontogenetic cell lineage from cell‐type phylogeny, whereby explicating that cell types can share common descent regardless of their structure, function or developmental origin. The article succinctly summarizes current progress and opinion in this field and formulates a more generalistic view of biological cell types as avatars, transient or terminal cell states deployed in a continuum of states by the developmental programme of one and the same omnipotent cell, capable of changing or combining identities with distinct evolutionary histories or inventing ad hoc identities that never existed in evolution or development. It highlights how the new logic grounded in the regulatory nature of cell identity transforms the concepts of cell homology and phenotypic stability, suggesting that cellular evolution is inherently and massively network‐like, with one‐to‐one homologies being rather uncommon and restricted to shallower levels of the animal tree of life.
