Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis

Higher expression of ED1 seems to correlate with the capacity of postnatal microglia to engulf synapses.

“However, a higher expression of ED1 seems to correlate with the capacity of postnatal microglia to engulf synapses (Schafer et al., 2012).”

• cites Schafer et al., 2012Not checked yet

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Microglial processes are highly motile.

“Microglial processes are highly motile (Davalos et al., 2005; Nimmerjahn et al., 2005)”

• cites Davalos et al., 2005Not checked yet

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• cites Nimmerjahn et al., 2005Not checked yet

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Macrophages from mice deficient in CD68 have no defects in phagocytosis of bacteria.

“and macrophages from mice deficient in CD68 have no defects in phagocytosis of bacteria (Song et al., 2011).”

• cites Song et al., 2011Not checked yet

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Apoptotic cells can release signals to attract macrophages and dendritic cells, such as the extracellular nucleotides ATP and UTP.

“In addition, apoptotic cells can release signals to attract macrophages and DCs, such as the extracellular nucleotides ATP and UTP (Elliott et al., 2009).”

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In vitro, live imaging has determined that the clearance time to completely eliminate an apoptotic cell by microglia is 25-95 min in a co-culture system.

“In vitro, live imaging has determined that the clearance time to completely eliminate an apoptotic cell by microglia is 25–95 min in a co-culture system (Parnaik et al., 2000)”

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Few studies have attempted to quantify the extent of microglial phagocytosis in vivo.

“Furthermore, few studies have attempted to quantify the extent of microglial phagocytosis in vivo (Ashwell, 1990; Dalmau et al., 2003; Parnaik et al., 2000; Sierra et al., 2010)”

• cites Ashwell, 1990Not checked yet

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• cites Dalmau et al., 2003Not checked yet

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• cites Parnaik et al., 2000Not checked yet

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These clearance times are in agreement with a general 1-2 h clearance time for macrophages.

“These numbers are in agreement with a general 1–2 h clearance time for macrophages (Henson and Hume, 2006).”

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The function of CD68 is unknown.

“One major problem is that the function of CD68 is unknown.”

The number of apoptotic cells observed at a particular time point represents only a small fraction of the actual number of apoptotic cells generated.

“Thus, the number of apoptotic cells observed in particular time point represents only a small fraction of the actual number of apoptotic cells generated (or total number of cells which disappear).”

In vivo, the microglial clearance time of apoptotic cells in physiological conditions has been estimated to be 70-90 min.

“in vivo, the microglial clearance time of apoptotic cells in physiological conditions has been estimated to be 70–90 min (Sierra et al., 2010).”

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The lack of molecular tools to specifically block recognition, engulfment, and degradation has precluded understanding of the global impact of microglial phagocytosis in vivo.

“However, the lack of molecular tools to specifically block these three steps has precluded our understanding of the global impact of microglial phagocytosis in vivo.”

Detection of apoptotic cell-associated cellular patterns, of which phosphatidylserine exposure in the outer leaflet is the main exponent, is mediated directly by several receptors including BAI-1 and by bridging molecules such as MFG-E8.

“Detection of apoptotic cells-associated cellular patterns (ACAMPs), of which exposure of phosphatidylserine (PS) in the outer leaflet of the cell membrane is the main exponent, is mediated directly by several receptors, including brain-specific angiogenesis inhibitor 1 [BAI-1; reviewed in Armstrong and Ravichandran (2011)], and by bridging molecules such as milk fat globule-epidermal growth factor”

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In microglia, UDP acts on P2Y6 receptors to facilitate phagocytosis.

“In microglia, UDP, the product of degradation of UTP by extracellular ectonucleotidases, acts on P2Y6 receptors to facilitate phagocytosis (Koizumi et al., 2007).”

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Many in vivo experiments rely on the use of phagocytosis markers such as CD68 (ED1 or macrosialin) as a proxy.

“In fact, many in vivo experiments rely on the use of phagocytosis “markers” such as CD68 (ED1 or macrosialin) as a proxy.”

The constant surveillance of the brain parenchyma by microglial processes supports their capacity to fortuitously encounter targets to engulf.

“and their constant surveillance of the brain parenchyma supports their capacity to fortuitously encounter targets to engulf.”

TREM2 loss of function prevents microglial phagocytosis.

“Another important receptor that signals internalization is triggering receptor expressed on myeloid cells-2 (TREM2), whose loss of function prevents microglial phagocytosis (Takahashi et al., 2005; Hsieh et al., 2009).”

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• cites Hsieh et al., 2009Not checked yet

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Another important chemotactic signal released by apoptotic cells is fractalkine/CX3CL1.

“Another important chemotactic signal released by apoptotic cells is fractalkine/CX3CL1 (Truman et al., 2008; Noda et al., 2011).”

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• cites Noda et al., 2011Not checked yet

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Phagocytes are equipped with a complementary array of receptors that enable them to recognize targets and discriminate them from the remaining parenchyma, particularly from living cells.

“Phagocytes are equipped with a likely complementary array of receptors which enable them to recognize their targets (the so-called “eat-me” signals) and discriminate them from the remaining parenchyma, particularly from living cells (which express “don't-eat-me” signals) (Savill et al., 2002; Ravichandran, 2010).”

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• cites Ravichandran, 2010Not checked yet

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Microglia are not replaced during the postnatal period and later life by liver- or bone marrow-derived macrophages.

“In contrast to other yolk sac-derived macrophages, they are not replaced during the postnatal period and later life by liver- or bone marrow-derived macrophages (Hoeffel et al., 2012).”

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In most studies, microglial phagocytosis is assessed exclusively in vitro, using primary or transformed microglial cells fed with targets such as latex beads, apoptotic cells, cell debris, or Aβ.

“One major limitation is that in most studies, microglial phagocytosis is assessed exclusively in vitro, utilizing a model of phagocytosis in which primary or transformed microglial cells are “fed” with a variety of targets, ranging from latex beads to primary or transformed apoptotic cells, cell debris, or Aβ.”

Anti-CD68 antibodies do not block macrophage phagocytosis in vitro.

“While located in the lysosomal compartment, anti-CD68 antibodies do not block macrophage phagocytosis in vitro (Damoiseaux et al., 1994)”

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Engulfment can also be triggered by soluble opsonins that bind to receptors signaling internalization in microglia.

“In addition to the direct recognition of the targets by microglial cell membrane receptors, engulfment can also triggered by soluble opsonins that bind to receptors signaling internalization in the microglia.”

The rapid clearance time of dead cells is likely behind the qualitative rather than quantitative assessment of microglial phagocytosis.

“The rapid clearance time of dead cells is likely behind this qualitative rather than quantitative assessment.”

Small puncta of apoptotic cell material are observed within branches of ramified microglia in fixed adult hippocampus, indirectly suggesting their transport.

“small puncta of apoptotic cell material are observed within branches of ramified microglia in fixed adult hippocampus, indirectly suggesting their transport (Sierra et al., 2010).”

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In C. elegans, microglial vATPases are required for phagosome-lysosome fusions and consequently to degrade cargo.

“A recent study in C. elegans using live imaging showed that in this nematode microglial vATPases are required for phagosome–lysosome fusions and consequently to degrade cargo (Peri and Nusslein-Volhard, 2008).”

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Blockade of microglial phagocytosis of polymorphonuclear neutrophils that infiltrate the brain parenchyma after focal ischemia decreases neuronal viability in organotypic slices.

“Further, blockade of microglial phagocytosis of polymorphonuclear neutrophils, which infiltrate the brain parenchyma after focal ischemia, decreases neuronal viability in organotypic slices (Neumann et al., 2008).”

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Phagocytosis of apoptotic neurons is beneficial for neuronal survival.

“Phagocytosis of apoptotic neurons is also beneficial for neuronal survival.”

Removal of axonal debris by microglia increases axonal regeneration in vitro.

“and removal of axonal debris by microglia increases axonal regeneration in vitro (Tanaka et al., 2009; Hosmane et al., 2012).”

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• cites Hosmane et al., 2012Not checked yet

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Once contact is established, the signal is transduced by intracellular kinases such as Syk and phosphatidylinositol 3-kinase, small GTPases such as Rac and Rho, and adapter molecules such as the ELMO family.

“so that once the contact is established the signal is transduced by a variety of intracellular kinases (Syk kinase, phosphatidylinositol 3-kinase) and small GTPases (Rac, Rho) and adapter molecules such as engulfing and cell motility (ELMO) family (Gumienny et al., 2001; Lee et al., 2007).”

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• cites Lee et al., 2007Not checked yet

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The acidic pH found in phagolysosomes (pH ≤ 5) is essential for lysosomal degradation capabilities.

“The acidic pH found in phagolysosomes (pH ≤ 5) is essential for the lysosomal degradation capabilities, as it is optimal for most hydrolases.”

Phagocytosis is not only performed by ameboid, activated cells but also by terminal or en passant branches of ramified, resting microglia.

“Moreover, because phagocytosis is not only performed by ameboid, activated cells but also by terminal or en passant branches of ramified, resting microglia (Peri and Nusslein-Volhard, 2008; Sierra et al., 2010)”

• cites Peri and Nusslein-Volhard, 2008Not checked yet

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• cites Sierra et al., 2010Not checked yet

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Phagocytosis of apoptotic neutrophils and T cells during resolution of the inflammatory response prevents the release of intracellular granules containing lysosomal enzymes and possibly acidification of the extracellular space.

“For instance, the phagocytosis of apoptotic neutrophils and T cells during the resolution of the inflammatory response prevents the release of intracellular granules containing lysosomal enzymes and possibly acidification of the extracellular space (Magnus et al., 2001).”

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In normal conditions, microglia do not express MHC-II.

“In normal conditions, microglia do not express MHC-II and only a subpopulation expresses co-stimulatory molecules such as CD11c (Bulloch et al., 2008)”

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In normal conditions, only a subpopulation of microglia expresses co-stimulatory molecules such as CD11c.

“In normal conditions, microglia do not express MHC-II and only a subpopulation expresses co-stimulatory molecules such as CD11c (Bulloch et al., 2008)”

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Live imaging experiments show that resembling phagosomal cups are retrogradely transported to the cell soma in the mouse neocortex.

“Live imaging experiments show that resembling phagosomal cups are retrogradely transported to the cell soma in the mouse neocortex (Nimmerjahn et al., 2005)”

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Collectively, these data indirectly suggest a yet unexplored role of the cytoskeleton in transporting the phagosome for the degradation of the engulfed material.

“Collectively, these data indirectly suggest a yet unexplored role of the cytoskeleton in transporting the phagosome for the degradation of the engulfed material.”

Direct evidence of retrograde transport of cargo-containing phagosomes was recently found in C. elegans.

“Direct evidence of retrograde transport of cargo-containing phagosomes was recently found in C. elegans (Peri and Nusslein-Volhard, 2008).”

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Myelin debris contains inhibitory molecules that inhibit axonal regeneration.

“In addition, myelin debris contains inhibitory molecules which inhibit axonal regeneration (Gitik et al., 2011)”

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Upon local inflammatory challenge, microglia show increased expression of MHC-II and CD11c in vivo.

“Upon local inflammatory challenge, microglia show increased expression of MHC-II and CD11c in vivo and increased antigen presentation in vitro, albeit with much lower efficiency than professional APCs (Gottfried-Blackmore et al., 2009).”

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Ingestion and degradation of targets has several indirect consequences for the phagocyte as well as the surrounding tissue.

“Furthermore, ingestion and degradation of targets has several indirect consequences for the phagocyte as well as the surrounding tissue.”

Microglia have poor antigen presenting activity in vivo.

“and in agreement they have poor antigen presenting activity in vivo (Ford et al., 1995).”

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The rapid clearance of apoptotic cells prevents their transformation into secondary necrotic cells, with subsequent loss of permeability of cell membranes and spillover of intracellular contents.

“The rapid clearance of apoptotic cells prevents their transformation into secondary necrotic cells (as it readily occurs in vitro), with the subsequent loss of permeability of the cell membranes and spillover of intracellular contents.”

Direct evidence of the beneficial effects of microglial phagocytosis was shown recently in a mouse model of Rett syndrome by knocking out the methyl-CpG-binding protein Mecp2.

“Direct evidence of the beneficial effects of microglial phagocytosis was shown recently in a mouse model of Rett syndrome by knocking out the methyl-CpG-binding protein Mecp2 (Derecki et al., 2012).”

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Signaling associated with the acidic pH of lysosomes deactivates the generation of radicals from the oxidative burst.

“Interestingly, the signaling associated with the acidic pH of lysosomes deactivates the generation of radicals from the oxidative burst (Li et al., 2010).”

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Microglia receive a tremendous metabolic load from lipids, carbohydrates, proteins, and other components from the digested target, leading to direct changes in the phagocyte's lipid and cholesterol, and possibly glucose metabolism.

“In addition, microglia receive a tremendous metabolic load from the lipids, carbohydrates, proteins, and other components from the digested target (particularly in the case of apoptotic cells and microorganisms), leading to direct changes in the phagocyte's lipid and cholesterol, and possibly glucose metabolism (Han and Ravichandran, 2011).”

• cites Han and Ravichandran, 2011Not checked yet

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In the living brain, the beneficial effects of microglial phagocytosis have been harder to prove, possibly due to the lack of molecular tools to specifically interfere with microglial phagocytosis.

“In the living brain, however, the beneficial effects of microglial phagocytosis have been harder to prove, possibly due to the lack of molecular tools to specifically interfere with microglial phagocytosis.”

These pathways lead to remodeling of the phagocyte cytoskeleton through actin polymerization and membrane composition, triggering formation of pseudopodia that form a phagocytic cup engulfing the target.

“These pathways lead to the remodeling of the phagocyte cytoskeleton through actin polymerization and membrane composition, triggering the formation of pseudopodia that form a phagocytic cup engulfing the target (Lee et al., 2007).”

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Neurons can be rescued from excitotoxic death when phagocytosis is promoted by the chemokine fractalkine in neuron-microglia co-cultures, but not in neuronal cultures alone.

“For instance, neurons can be rescued from excitotoxic death when phagocytosis is promoted by the chemokine fractalkine in neuron-microglia co-cultures, but not in neuronal cultures alone (Noda et al., 2011).”

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Overall, phagocytosis is considered to be essential for maintaining brain tissue homeostasis.

“Overall, phagocytosis is considered to be essential for maintaining brain tissue homeostasis.”

In the juvenile visual cortex, most microglia interact with synaptic elements (spines, axon terminals, perisynaptic astrocytes, and synaptic clefts).

“In the juvenile visual cortex, most microglia interact with synaptic elements (spines, axon terminals, perisynaptic astrocytes, and synaptic clefts) (Tremblay et al., 2010).”

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In MS, myelin-specific T cells may escape from tolerance and enter the brain under some circumstances, leading to demyelination.

“In the autoimmune disease MS, however, myelin-specific T cells may escape from this tolerance mechanism and enter the brain under some circumstances, leading to demyelination (Goverman, 2011).”

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Pruning in the dorsal lateral geniculate nucleus is at least partially mediated by complement-mediated microglial phagocytosis.

“This pruning is at least partially mediated by complement-mediated microglial phagocytosis, because mice deficient either for the receptor CR3 or its ligand, C3, have decreased phagocytosis of synaptic inputs, a sustained increase in synaptic density, and deficits in segregation of the eye-specific territories compared to wild-type mice (Schafer et al., 2012).”

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Microglia phagocytosing apoptotic T cells produce less TNFα than naïve microglia after LPS challenge in vitro.

“Microglia phagocytosing apoptotic T cells produce less tumor necrosis factor alpha (TNFα), a major pro-inflammatory cytokine, than naïve microglia after LPS challenge in vitro (Magnus et al., 2001).”

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Inflammation-induced respiratory burst leads to the release of glutamate by microglia, further contributing to neuronal damage.

“In turn, inflammation-induced respiratory burst leads to the release of glutamate by microglia, further contributing to neuronal damage (Barger et al., 2007).”

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Upon local inflammatory challenge, microglia show increased antigen presentation in vitro, albeit with much lower efficiency than professional APCs.

“Upon local inflammatory challenge, microglia show increased expression of MHC-II and CD11c in vivo and increased antigen presentation in vitro, albeit with much lower efficiency than professional APCs (Gottfried-Blackmore et al., 2009).”

• cites Gottfried-Blackmore et al., 2009Not checked yet

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If phagocytosis is too effective, it may lead to the removal of cells which will otherwise have time to repair themselves.

“It has been suggested that if phagocytosis is too effective, it may lead to the removal of cells which will otherwise have time to repair themselves (Kao et al., 2011).”

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The microglial contribution to antigen presentation in vivo is thought to be mostly irrelevant.

“the microglial contribution to antigen presentation in vivo is thought to be mostly irrelevant (Galea et al., 2007; Ransohoff and Engelhardt, 2012).”

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• cites Ransohoff and Engelhardt, 2012Not checked yet

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A M2 phenotype induced by glioma cancer stem cells reduces phagocytosis.

“whereas a M2 phenotype induced by glioma cancer stem cells reduces phagocytosis (Wu et al., 2010).”

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Phagocytosis is the de facto mechanism to discriminate between moribund and dead cells.

“Nevertheless, these evidences suggest that, since there are no stop points in apoptosis analog to the check points found in mitosis, phagocytosis is the de facto mechanism to discriminate between moribund and dead cells.”

Microglia play a negative role in the disease progression of EAE, as its depletion reduces the severity of the disease.

“Microglia seems to play a negative role in the disease progression of EAE, the animal model of MS, as its depletion reduces the severity of the disease (Heppner et al., 2005).”

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A M2 phenotype driven by IL-4 and IL-13 increases the phagocytosis of myelin.

“On the other hand, a M2 phenotype driven by IL-4 and IL-13 increases the phagocytosis of myelin (Durafourt et al., 2012)”

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In the ischemic cerebral cortex, microglial contacts with synaptic boutons last longer (1 h) than in the control cortex (5 min).

“In the ischemic cerebral cortex microglial contacts with synaptic boutons last-longer (1 h) than in the control cortex (5 min) (Wake et al., 2009).”

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In microglia, the respiratory burst appears to be activated by phagocytosis through similar mechanisms after phagocytosis of zymosan or myelin.

“In microglia, the respiratory burst appears to be activated by phagocytosis through similar mechanisms (Ueyama et al., 2004) after phagocytosis of zymosan (a yeast cell wall preparation) (Newell et al., 2007) or myelin (Williams et al., 1994)”

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• cites Newell et al., 2007Not checked yet

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• cites Williams et al., 1994Not checked yet

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Microglia have the capacity to present antigens under some particular conditions.

“While it is clear that they have the capacity of presenting antigens under some particular conditions”

Throughout lifetime the excess of photoreceptors membrane shredded is phagocytosed by retinal pigment epithelium cells.

“and throughout lifetime the excess of photoreceptors membrane shredded is phagocytosed by retinal pigment epithelium (RPE) cells (Kevany and Palczewski, 2010).”

• cites Kevany and Palczewski, 2010Not checked yet

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The phagocytic capacity is region-specific, as microglia only phagocytose 50% of the apoptotic cells at the maximum period of cell death (P3) in the developing cerebellum.

“Nonetheless, the phagocytic capacity is region-specific, as microglia only phagocytose 50% of the apoptotic cells at the maximum period of cell death (P3) in the developing cerebellum (Ashwell, 1990; Marin-Teva et al., 2004; Wakselman et al., 2008).”

• cites Ashwell, 1990Not checked yet

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• cites Marin-Teva et al., 2004Not checked yet

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• cites Wakselman et al., 2008Not checked yet

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Other cell types mediate phagocytosis of apoptotic cells in vivo during development.

“Nonetheless, other cell types mediate phagocytosis of apoptotic cells in vivo during development.”

In the developing retina, phagocytosis is executed by microglia and Müller cells.

“In the developing retina, phagocytosis is executed by microglia and Müller cells (Egensperger et al., 1996)”

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In vitro, microglia produce several components of the complement cascade, including C1q and C3, which are involved in the phagocytosis of neurites via CR3.

“In vitro, microglia produce several components of the complement cascade, including C1q and C3, which are involved in the phagocytosis of neurites via CR3 (Linnartz et al., 2012).”

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Removal of the monosaccharide sialic acid from the neural glycocalyx is essential for C1q binding to neurites and subsequent microglial phagocytosis in cultured neurons.

“Interestingly, removal of the monosaccharide sialic acid from the neural glycocalyx is essential for C1q binding to neurites and subsequent microglial phagocytosis in cultured neurons (Linnartz et al., 2012).”

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Classic activation paradigms driving a M1 phenotype lead to increased enhanced engulfment of apoptotic cells in vitro.

“For instance, classic activation paradigms driving a M1 phenotype lead to increased enhanced engulfment of apoptotic cells in vitro (Chan et al., 2001; McArthur et al., 2010).”

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• cites McArthur et al., 2010Not checked yet

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The microglial respiratory burst has been linked to induction of neuronal apoptosis in the developing cerebellum in vitro and in the developing hippocampus in vivo.

“Interestingly, the microglial respiratory burst has been linked to induction of neuronal apoptosis in the developing cerebellum in vitro (Marin-Teva et al., 2004) and in the developing hippocampus in vivo (Wakselman et al., 2008).”

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• cites Wakselman et al., 2008Not checked yet

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In the developing cerebellum (P7), phagocytosis of apoptotic oligodendrocytes is carried out by specialized astrocytes, the Bergmann glia, albeit at a relative low efficiency (55% of apoptotic cells engulfed).

“For instance, in the developing cerebellum (P7) phagocytosis of apoptotic oligodendrocytes is carried out by specialized astrocytes, the Bergmann glia, albeit at a relative low efficiency (55% of apoptotic cells engulfed) (Parnaik et al., 2000).”

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A detailed map estimating microglial phagocytosis during development showed an overall high efficiency of microglia-removing apoptotic cells.

“A detailed map estimating microglial phagocytosis during development showed an overall high efficiency of microglia-removing apoptotic cells (Dalmau et al., 2003).”

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Phagocytosis of apoptotic cells is largely anti-inflammatory.

“Over the past 20 years, it has been made clear that the phagocytosis of apoptotic cells is largely anti-inflammatory (Stern et al., 1996; Voll et al., 1997; Fadok et al., 1998).”

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• cites Voll et al., 1997Not checked yet

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• cites Fadok et al., 1998Not checked yet

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Direct, quantified evidence of microglia phagocytosing synapses (mostly presynaptic elements) in the developing visual system has been provided using confocal and electron microscopy.

“Direct, quantified evidence of microglia phagocytosing synapses (mostly, presynaptic elements) in the developing visual system has been recently provided using confocal and electron microscopy (Schafer et al., 2012).”

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Overall, these data support a novel role for microglia in monitoring synapses in the healthy developing brain.

“Overall, these data support a novel role for microglia in monitoring synapses in the healthy developing brain, with potentially profound consequences for diseases in which neural connectivity and microglial activation concur.”

Resting or steady-state microglia are efficient phagocytes of spines and apoptotic cells during physiological conditions in the adult and developing brain.

“the notion that microglia require to be preactivated to phagocytose efficiently is challenged by a number of recent papers showing that “resting” or “steady-state” microglia are efficient phagocytes of spines and apoptotic cells during physiological conditions in the adult and developing brain (Dalmau et al., 2003; Sierra et al., 2010; Schafer et al., 2012)”

• cites Dalmau et al., 2003Not checked yet

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• cites Sierra et al., 2010Not checked yet

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• cites Schafer et al., 2012Not checked yet

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The anti-phlogistic response to phagocytosis of apoptotic cells also occurs in microglia.

“The anti-phlogistic response to phagocytosis of apoptotic cells also occurs in microglia.”

Spines contacted by microglia were more frequently eliminated than non-contacted spines.

“live imaging indirectly supported a role for microglia in pruning synapses, as spines contacted by microglia where more frequently eliminated than non-contacted spines (Tremblay et al., 2010).”

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HMGB1 is released during ischemia in stroke patients and in mice subjected to MCAO.

“HMGB1 is also released during ischemia (assumedly, from the necrotic core) in stroke patients and in mice subjected to MCAO, launched an inflammatory response, which is detrimental for neuronal survival (Kim et al., 2006; Muhammad et al., 2008).”

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• AssumptionThe authors state this as an assumption: HMGB1 released during ischemia originates from the necrotic core.

HMGB1 released during ischemia launches an inflammatory response that is detrimental for neuronal survival.

“HMGB1 is also released during ischemia (assumedly, from the necrotic core) in stroke patients and in mice subjected to MCAO, launched an inflammatory response, which is detrimental for neuronal survival (Kim et al., 2006; Muhammad et al., 2008).”

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• AssumptionThe authors state this as an assumption: HMGB1 released during ischemia originates from the necrotic core.

In vitro, low concentrations of Aβ (1-42) (nanomolar range) lead to activation of microglia and an inflammatory response that is partly responsible for neuronal damage.

“In vitro, low concentrations of Aβ (1–42) (nanomolar range) lead to activation of microglia and an inflammatory response, which is partly responsible for neuronal damage (Maezawa et al., 2011).”

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Recognition of S. cerevisiae β-glucans (such as zymosan) is mediated by Dectin1, CR3, and the mannose receptor (MR, CD206).

“recognition of S. cerevisiae β-glucans (such as zymosan) is mediated by Dectin1, CR3, and the mannose receptor (MR, CD206) (Hadas et al., 2010)”

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Recognition of TLR2 and TLR4 ligands enhances phagocytosis.

“recognition of their ligands enhances phagocytosis (Ribes et al., 2010; Kochan et al., 2012)”

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HMGB1 is not released by apoptotic cells even when they fail to be phagocytosed and transform into secondary necrotic cells.

“It is worth noting that HMGB1 is not released by apoptotic cells even when they fail to be phagocytosed and transform into secondary necrotic cells (Scaffidi et al., 2002).”

• cites Scaffidi et al., 2002Not checked yet

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Phagocytosis of necrotic PCD Jurkat cells reduces the release of TNFα by microglia.

“Others have shown that the phagocytosis of necrotic PCD Jurkat cells reduces the release of TNFα by microglia (Hirt and Leist, 2003).”

• cites Hirt and Leist, 2003Not checked yet

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Recognition of E. coli LPS is mediated by TLR4.

“recognition of E. coli LPS is mediated by TLR4 (Sivagnanam et al., 2010)”

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Death of living cells by phagocytosis (phagoptosis) might contribute to the pathophysiology of some diseases where inflammation occurs.

“Death of living cells by phagocytosis, recently termed “phagoptosis,” might contribute to the pathophysiology of some diseases where inflammation, the main trigger for phagoptosis, occurs.”

• AssumptionRests on an assumption: Inflammation is the main trigger for phagoptosis.

Phagosomes were found within microglial cells up to 7 days after E. coli injection.

“In contrast, phagosomes were found within microglial cells up to 7 days after (Kaur et al., 2004)”

• cites Kaur et al., 2004Not checked yet

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Phagocytosis of bacteria activates the inflammatory cascade in microglia, inducing expression of pro-inflammatory cytokines (TNFα), TLRs (TLR4, TLR9), complement receptors (CR3), scavenger receptors (SRA), and MHC-II.

“Phagocytosis of bacteria activates the inflammatory cascade in microglia, inducing the expression of pro-inflammatory cytokines (TNFα), TLRs (TLR4, TLR9), complement receptors (CR3), scavenger receptors (SRA), and MHC-II (Sivagnanam et al., 2010).”

• cites Sivagnanam et al., 2010Not checked yet

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TLR2 and TLR4 are constitutively expressed by microglia.

“TLR2 and 4 are constitutively expressed by microglia (Bsibsi et al., 2002)”

• cites Bsibsi et al., 2002Not checked yet

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TAMs contribute to glioma progression by enhancing tumor migration and proliferation through growth factors, angiogenic molecules, and enzymes degrading the extracellular matrix.

“On the other hand, TAMs contribute to glioma progression by enhancing tumor migration and proliferation through growth factors, angiogenic molecules, and enzymes degrading the extracellular matrix (Watters et al., 2005).”

• cites Watters et al., 2005Not checked yet

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The clearance time for phagoptotic neurons is likely to be longer than for phagocytosed apoptotic neurons.

“We argue that the clearance time for phagoptotic neurons is likely to be longer than for phagocytosed apoptotic neurons, because phagoptotic cells fail to activate caspases and other mechanisms of self-destruction and rely exclusively on microglia for degradation (Brown and Neher, 2012).”

• cites Brown and Neher, 2012Not checked yet

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Engulfing a live neuron may take microglia under 2 h.

“Time-lapse imaging experiments suggest that engulfing a live neuron may take microglia under 2 h (Neher et al., 2011) (Figure 4), however the time to fully degrade it has not been estimated.”

• cites Neher et al., 2011Not checked yet

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Glioma-initiating cells contribute to the recruitment of TAMs into the tumor mass.

“glioma-initiating cells contribute to the recruitment of TAMs into the tumor mass (Yi et al., 2011)”

• cites Yi et al., 2011Not checked yet

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Death by apoptosis has been documented in AD patients and in animal models of AD.

“Nonetheless, death by apoptosis has been documented in AD patients and in animal models of AD, although it is assumed to occur at low levels over a long period of time (Shimohama, 2000).”

• cites Shimohama, 2000Not checked yet

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• AssumptionThe authors state this as an assumption: Apoptosis in AD patients and animal models occurs at low levels over a long period of time.

The data on microglial phagocytosis of microorganisms suggests a high capacity to fight against brain infections such as meningitis.

“Although the data on microglial phagocytosis of microorganisms is not abundant, it seems to suggest a high capacity to fight against brain infections such as meningitis.”

The best-known case of a phagocytic system disease is the relatively rare but lethal Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), due to loss-off-function mutations of TREM2 and/or DAP12.

“In addition, the best-known case of a phagocytic system disease is the relatively rare but lethal Nasu–Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), due to loss-off-function mutations of TREM2 and/or DAP12 (Paloneva et al., 2002).”

• cites Paloneva et al., 2002Not checked yet

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Alzheimer's disease has a strong inflammatory component.

“For instance AD, which characterized at the histological level by plaques of Aβ as well as neurofibrillary tangles, has a strong inflammatory component (Johnston et al., 2011).”

• cites Johnston et al., 2011Not checked yet

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Microglia in the adult and developing brain are capable of phagocytosing many pathogens, including bacteria, yeast, and fungus.

“In the adult and developing brain, microglia are capable of phagocytosing many pathogens, including bacteria (Escherichia coli, Streptococcus pneumonia, Staphylococcus aureus, Enterococcus faecalis), yeast (Saccharomyces cerevisiae), and fungus (Candida albicans) (Kaur et al., 2004; Falsig et al., 2008; Shah et al., 2008; Hadas et al., 2010; Ribes et al., 2010; Peppoloni et al., 2011; Kochan et al”

• cites Kaur et al., 2004Not checked yet

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• cites Falsig et al., 2008Not checked yet

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• cites Shah et al., 2008Not checked yet

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When co-cultured with necrotic HT22 neurons, microglia express higher levels of pro-inflammatory cytokines (TNFα, IL-6), pro-inflammatory enzymes (nitric oxide synthase, 2-cyclooxygenase), MHC-II, and integrin CD11b through a mechanism involving MYD88.

“More recently, it has been shown that when co-cultured with necrotic HT22 neurons microglia do indeed express higher levels of pro-inflammatory cytokines (TNFα, IL-6), pro-inflammatory enzymes (nitric oxide synthase, 2-cyclooxygenase), MHC-II, and the integrin CD11b through a mechanism involving MYD88, a TLR adapter protein (Pais et al., 2008).”

• cites Pais et al., 2008Not checked yet

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Recognition of S. aureus peptidoglycan is mediated by TLR2.

“recognition of S. aureus peptidoglycan is mediated by TLR2 (Kielian et al., 2005)”

• cites Kielian et al., 2005Not checked yet

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Microglial phagocytosis may be the primary cause of cell death under some circumstances.

“Going further, microglial phagocytosis may be the primary cause of cell death under some circumstances.”

Glioma cells are rarely phagocytosed by TAMs in mouse models of glioma.

“Unfortunately, glioma cells are rarely phagocytosed by TAMs in mouse models of glioma (Galarneau et al., 2007).”

• cites Galarneau et al., 2007Not checked yet

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DAP12-deficient mice do not reflect the human neurodegenerative pathology.

“The contribution of microglia to the pathology of PLOSL remains obscure because DAP12-deficient mice do not reflect the human neurodegenerative pathology.”

Degradation and killing of living microorganisms is a time-consuming process.

“suggesting that degradation and killing of living microorganisms is a time-consuming process”

• cites Kaur et al., 2004Not checked yet

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Glioma-initiating cells polarize TAMs toward a M2 phenotype.

“polarize them toward a M2 phenotype (Wu et al., 2010)”

• cites Wu et al., 2010Not checked yet

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In a mouse model of neonatal stroke by medial cerebral artery occlusion, apoptotic neurons are poorly phagocytosed by activated microglia compared to the contralateral healthy hemisphere, where less apoptosis occurs.

“For instance, there is qualitative evidence that apoptotic neurons in a mouse model of neonatal stroke by medial cerebral artery occlusion (MCAO) are poorly phagocytosed by activated microglia compared to the contralateral healthy hemisphere, where less apoptosis occurs (Faustino et al., 2011).”

• cites Faustino et al., 2011Not checked yet

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In some forms of necrotic PCD, exposure of PS by calcium-independent signals triggers recognition of necrotic cells by macrophages and microglia.

“For instance, in some forms of necrotic PCD, exposure of PS by calcium-independent signals triggers recognition of necrotic cells by macrophages and microglia (Hirt et al., 2000; Hirt and Leist, 2003).”

• cites Hirt et al., 2000Not checked yet

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• cites Hirt and Leist, 2003Not checked yet

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Peripheral blood monocytes from PD patients, compared to age-matched controls, exhibit decreased phagocytosis of latex beads ex vivo.

“Moreover, peripheral blood monocytes from PD patients, compared to age-matched controls, exhibit decreased phagocytosis of latex beads ex vivo (Salman et al., 1999)”

• cites Salman et al., 1999Not checked yet

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Microglia phagocytose tumor cells that have been previously induced to apoptosis with etoposide or UV light.

“microglia do phagocytose tumor cells which have been previously induced apoptosis with the cytotoxic agent etoposide (Chang et al., 2000) or UV light (Kulprathipanja and Kruse, 2004)”

• cites Chang et al., 2000Not checked yet

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• cites Kulprathipanja and Kruse, 2004Not checked yet

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γ-secretase inhibitors prevent microglial Aβ engulfment.

“Similarly, γ-secretase inhibitors prevent microglial Aβ engulfment (Farfara et al., 2011).”

• cites Farfara et al., 2011Not checked yet

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In vitro co-culture with tumor cells decreases bead phagocytosis by microglia after a transient increase.

“in vitro studies have shown that co-culture with tumor cells decreases bead phagocytosis after a transient increase (Voisin et al., 2010)”

• cites Voisin et al., 2010Not checked yet

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Myelin inhibits its own phagocytosis through myelin CD47 binding to microglia and macrophage signal regulatory protein α (SIRPα).

“Furthermore, myelin inhibits its own phagocytosis through myelin CD47 binding to microglia and macrophages signal regulatory protein α (SIRPα) (Gitik et al., 2011).”

• cites Gitik et al., 2011Not checked yet

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In PNS lesions, myelinating Schwann cells are the major phagocytic population in the first few days, followed by invading macrophages.

“In PNS lesions, the myelinating Schwann cells are the major phagocytic population in the first few days, followed by invading macrophages (Hirata and Kawabuchi, 2002).”

• cites Hirata and Kawabuchi, 2002Not checked yet

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APP mRNA is not found in microglia of human AD brains.

“APP mRNA is not found in microglia of human AD brains (Scott et al., 1993)”

• cites Scott et al., 1993Not checked yet

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In vitro, microglia recognize and engulf fluorescently labeled fibrillary Aβ through a variety of receptors, including scavenger receptors, TLR2, and CD14.

“In vitro, microglia recognizes and engulfs fluorescently labeled fibrillary Aβ through a variety of receptors, including scavenger receptors (Paresce et al., 1996), TLR2 (Liu et al., 2012), and the TLR4-interacting molecule, CD14 (Liu et al., 2005).”

• cites Paresce et al., 1996Not checked yet

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• cites Liu et al., 2012Not checked yet

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• cites Liu et al., 2005Not checked yet

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The mechanisms of recognition of axonal debris seem to be different from those of apoptotic cells.

“Interestingly, the mechanisms of recognition of axonal debris seem to be different from those of apoptotic cells (Tanaka et al., 2009).”

• cites Tanaka et al., 2009Not checked yet

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In cortical explants where growing neurites were sectioned, the debris was cleared by added microglia.

“In cortical explants where growing neurites were sectioned, the debris was cleared by added microglia (Tanaka et al., 2009).”

• cites Tanaka et al., 2009Not checked yet

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Ablation experiments have suggested that the Aβ burden is cleared by blood-borne macrophages, but not resident microglia.

“ablation experiments have suggested that the Aβ burden is cleared by blood-borne macrophages, but not resident microglia (Simard et al., 2006)”

• cites Simard et al., 2006Not checked yet

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Microglia does not participate in the initial stages of plaque formation.

“strongly suggesting that microglia does not participate in the initial stages of plaque formation”

• cites Meyer-Luehmann et al., 2008Not checked yet

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Macrophages express Nogo receptors NgR1 and NgR2, which facilitate their migration out of the healing nerve, resulting in resolution of the inflammatory response.

“Importantly, macrophages express Nogo receptors NgR1 and NgR2, which facilitate their migration out of the healing nerve, thus resulting in the resolution of the inflammatory response (Fry et al., 2007).”

• cites Fry et al., 2007Not checked yet

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Efficient myelin clearance is an absolute requirement for recovery.

“therefore an efficient myelin clearance is an absolute requirement for recovery (Wang et al., 2002)”

• cites Wang et al., 2002Not checked yet

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Microglia is rapidly attracted to already formed plaques in a mouse model of AD with mutated APP and presenilin 1.

“Recent live imaging experiments have shown that microglia is rapidly attracted to already formed plaques in a mouse model of AD with mutated APP and presenilin 1 (a protein of the γ-secretase complex) (Meyer-Luehmann et al., 2008)”

• cites Meyer-Luehmann et al., 2008Not checked yet

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TAM phagocytosis of tumor cells is not very effective.

“While the literature confirms that TAM phagocytosis of tumor cells is not very effective”

Microglia can synthesize Aβ in vitro.

“While microglia can synthesize Aβ in vitro (Banati et al., 1993)”

• cites Banati et al., 1993Not checked yet

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Microglia from human glioblastoma patients have the capability of phagocytosing latex microbeads ex vivo.

“Microglia from human glioblastoma patients do have the capability of phagocytosing latex microbeads ex vivo (Hussain et al., 2006)”

• cites Hussain et al., 2006Not checked yet

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The fractalkine receptor has been found to contribute to the Aβ burden by some but not others.

“The fractalkine receptor, a regulator of phagocytosis, has been found to contribute to the Aβ burden by some (Lee et al., 2010; Liu et al., 2010) but not others (Fuhrmann et al., 2010).”

• cites Lee et al., 2010; Liu et al., 2010Not checked yet

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• cites Fuhrmann et al., 2010Not checked yet

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Myelin clearance after Wallerian degeneration is very inefficient in the CNS, contrary to the peripheral nervous system.

“Contrary to the peripheral nervous system (PNS), myelin clearance after WD is very inefficient in the CNS [reviewed in Gaudet et al. (2011)].”

• cites Gaudet et al. (2011)Not checked yet

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Macrophages have higher Aβ intake capacity than microglia in vitro.

“Macrophages have higher Aβ capacity intake than microglia in vitro (Lai and McLaurin, 2012)”

• cites Lai and McLaurin, 2012Not checked yet

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Microglia does not phagocytose Aβ in vivo.

“further suggesting that microglia does not phagocytose Aβ in vivo (Stalder et al., 2001)”

• cites Stalder et al., 2001Not checked yet

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Aβ induces a positive chemotaxis of microglia via TGFβ.

“Further, Aβ induces a positive chemotaxis of microglia via TGFβ (Huang et al., 2010), possibly explaining their location around plaques.”

• cites Huang et al., 2010Not checked yet

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In vivo, LPS administered locally either transiently reduced or enhanced Aβ load in mouse models of AD.

“In vivo, LPS administered locally either transiently reduced (Herber et al., 2004), or enhanced (Qiao et al., 2001) Aβ load in mouse models of AD.”

• cites Herber et al., 2004Not checked yet

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• cites Qiao et al., 2001Not checked yet

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Tumor cells evade phagocytosis by lacking appropriate "eat-me" signals in their membrane.

“Further, it seems that tumor cells evade phagocytosis by lacking in their membrane the appropriate “eat-me” signals.”

Myelin proteins such as Nogo interfere with axonal regeneration and repair.

“Myelin proteins such as Nogo are well-known to interfere with axonal regeneration and repair”

• cites Wang et al., 2002Not checked yet

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In culture, myelin-phagocytosing macrophages inhibit T cell proliferation, further containing the immune response.

“In culture, myelin-phagocytosing macrophages inhibit T cell proliferation, further containing the immune response (Bogie et al., 2011).”

• cites Bogie et al., 2011Not checked yet

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CNS regeneration after trauma does not occur.

“In contrast, CNS regeneration after trauma does not occur, and microglial poor phagocytosing capabilities together with poor or slow recruitment of macrophages are partly to blame (Gaudet et al., 2011).”

• cites Gaudet et al., 2011Not checked yet

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Rapid clearance of myelin and resolution of the immune response is greatly responsible for regeneration after nerve injury.

“The rapid clearance of myelin and resolution of the immune response is greatly responsible for regeneration after nerve injury.”

In vitro, microglia recognize and phagocytose myelin through CR3, SRA, and FcRs among other receptors.

“In vitro, microglia recognize and phagocytose myelin through CR3, SRA, and FcRs among other receptors (Smith, 2001).”

• cites Smith, 2001Not checked yet

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Microglial poor phagocytosing capabilities together with poor or slow recruitment of macrophages are partly to blame for the lack of CNS regeneration after trauma.

“microglial poor phagocytosing capabilities together with poor or slow recruitment of macrophages are partly to blame (Gaudet et al., 2011)”

• cites Gaudet et al., 2011Not checked yet

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Myelin debris is still observed in the human spinal cord years after injury.

“However, myelin debris is still observed in the human spinal cord years after the injury (Buss et al., 2004).”

• cites Buss et al., 2004Not checked yet

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Microglial phagocytosis has beneficial and detrimental consequences for tissue homeostasis.

“Like Janus, the roman god of war and peace, microglial phagocytosis has beneficial (e.g., anti-inflammatory) and detrimental (e.g., respiratory burst) consequences for tissue homeostasis which remain largely unexplored in vivo.”

A microglial phenotype supportive of remyelination has been described.

“More recently, a microglial phenotype supportive of remyelination has been described (Olah et al., 2012).”

• cites Olah et al., 2012Not checked yet

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