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

In the paper

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

What the sources say

• Not checked yetcites Schafer et al., 2012

In the paper

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

What the sources say

• Not checked yetcites Davalos et al., 2005
• Not checked yetcites Nimmerjahn et al., 2005

In the paper

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

What the sources say

• Not checked yetcites Song et al., 2011

In the paper

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

What the sources say

• Not checked yetcites Elliott et al., 2009

In the paper

“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)”

What the sources say

• Not checked yetcites Parnaik et al., 2000

In the paper

“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)”

What the sources say

• Not checked yetcites Ashwell, 1990
• Not checked yetcites Dalmau et al., 2003
• Not checked yetcites Parnaik et al., 2000

In the paper

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

What the sources say

• Not checked yetcites Henson and Hume, 2006

In the paper

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

In the paper

“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 the paper

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

What the sources say

• Not checked yetcites Sierra et al., 2010

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites Armstrong and Ravichandran (2011)

In the paper

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

What the sources say

• Not checked yetcites Koizumi et al., 2007

In the paper

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

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Takahashi et al., 2005
• Not checked yetcites Hsieh et al., 2009

In the paper

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

What the sources say

• Not checked yetcites Truman et al., 2008
• Not checked yetcites Noda et al., 2011

In the paper

“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).”

What the sources say

• Not checked yetcites Savill et al., 2002
• Not checked yetcites Ravichandran, 2010

In the paper

“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).”

What the sources say

• Not checked yetcites Hoeffel et al., 2012

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites Damoiseaux et al., 1994

In the paper

“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.”

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Sierra et al., 2010

In the paper

“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).”

What the sources say

• Not checked yetcites Peri and Nusslein-Volhard, 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Neumann et al., 2008

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Tanaka et al., 2009
• Not checked yetcites Hosmane et al., 2012

In the paper

“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).”

What the sources say

• Not checked yetcites Gumienny et al., 2001
• Not checked yetcites Lee et al., 2007

In the paper

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

In the paper

“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)”

What the sources say

• Not checked yetcites Peri and Nusslein-Volhard, 2008
• Not checked yetcites Sierra et al., 2010

In the paper

“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).”

What the sources say

• Not checked yetcites Magnus et al., 2001

In the paper

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

What the sources say

• Not checked yetcites Bulloch et al., 2008

In the paper

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

What the sources say

• Not checked yetcites Bulloch et al., 2008

In the paper

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

What the sources say

• Not checked yetcites Nimmerjahn et al., 2005

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Peri and Nusslein-Volhard, 2008

In the paper

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

What the sources say

• Not checked yetcites Gitik et al., 2011

In the paper

“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).”

What the sources say

• Not checked yetcites Gottfried-Blackmore et al., 2009

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Ford et al., 1995

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Derecki et al., 2012

In the paper

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

What the sources say

• Not checked yetcites Li et al., 2010

In the paper

“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).”

What the sources say

• Not checked yetcites Han and Ravichandran, 2011

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Lee et al., 2007

In the paper

“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).”

What the sources say

• Not checked yetcites Noda et al., 2011

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Tremblay et al., 2010

In the paper

“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).”

What the sources say

• Not checked yetcites Goverman, 2011

In the paper

“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).”

What the sources say

• Not checked yetcites Schafer et al., 2012

In the paper

“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).”

What the sources say

• Not checked yetcites Magnus et al., 2001

In the paper

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

What the sources say

• Not checked yetcites Barger et al., 2007

In the paper

“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).”

What the sources say

• Not checked yetcites Gottfried-Blackmore et al., 2009

In the paper

“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).”

What the sources say

• Not checked yetcites Kao et al., 2011

In the paper

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

What the sources say

• Not checked yetcites Galea et al., 2007
• Not checked yetcites Ransohoff and Engelhardt, 2012

In the paper

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

What the sources say

• Not checked yetcites Wu et al., 2010

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Heppner et al., 2005

In the paper

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

What the sources say

• Not checked yetcites Durafourt et al., 2012

In the paper

“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).”

What the sources say

• Not checked yetcites Wake et al., 2009

In the paper

“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)”

What the sources say

• Not checked yetcites Ueyama et al., 2004
• Not checked yetcites Newell et al., 2007
• Not checked yetcites Williams et al., 1994

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Kevany and Palczewski, 2010

In the paper

“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).”

What the sources say

• Not checked yetcites Ashwell, 1990
• Not checked yetcites Marin-Teva et al., 2004
• Not checked yetcites Wakselman et al., 2008

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Egensperger et al., 1996

In the paper

“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).”

What the sources say

• Not checked yetcites Linnartz et al., 2012

In the paper

“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).”

What the sources say

• Not checked yetcites Linnartz et al., 2012

In the paper

“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).”

What the sources say

• Not checked yetcites Chan et al., 2001
• Not checked yetcites McArthur et al., 2010

In the paper

“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).”

What the sources say

• Not checked yetcites Marin-Teva et al., 2004
• Not checked yetcites Wakselman et al., 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Parnaik et al., 2000

In the paper

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

What the sources say

• Not checked yetcites Dalmau et al., 2003

In the paper

“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).”

What the sources say

• Not checked yetcites Stern et al., 1996
• Not checked yetcites Voll et al., 1997
• Not checked yetcites Fadok et al., 1998

In the paper

“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).”

What the sources say

• Not checked yetcites Schafer et al., 2012

In the paper

“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.”

In the paper

“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)”

What the sources say

• Not checked yetcites Dalmau et al., 2003
• Not checked yetcites Sierra et al., 2010
• Not checked yetcites Schafer et al., 2012

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites Tremblay et al., 2010

In the paper

“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).”

What the sources say

• Not checked yetcites Kim et al., 2006; Muhammad et al., 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Kim et al., 2006; Muhammad et al., 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Maezawa et al., 2011

In the paper

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

What the sources say

• Not checked yetcites Hadas et al., 2010

In the paper

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

What the sources say

• Not checked yetcites Ribes et al., 2010; Kochan et al., 2012

In the paper

“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).”

What the sources say

• Not checked yetcites Scaffidi et al., 2002

In the paper

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

What the sources say

• Not checked yetcites Hirt and Leist, 2003

In the paper

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

What the sources say

• Not checked yetcites Sivagnanam et al., 2010

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites Kaur et al., 2004

In the paper

“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).”

What the sources say

• Not checked yetcites Sivagnanam et al., 2010

In the paper

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

What the sources say

• Not checked yetcites Bsibsi et al., 2002

In the paper

“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).”

What the sources say

• Not checked yetcites Watters et al., 2005

In the paper

“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).”

What the sources say

• Not checked yetcites Brown and Neher, 2012

In the paper

“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.”

What the sources say

• Not checked yetcites Neher et al., 2011

In the paper

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

What the sources say

• Not checked yetcites Yi et al., 2011

In the paper

“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).”

What the sources say

• Not checked yetcites Shimohama, 2000

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites Paloneva et al., 2002

In the paper

“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).”

What the sources say

• Not checked yetcites Johnston et al., 2011

In the paper

“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”

What the sources say

• Not checked yetcites Kaur et al., 2004
• Not checked yetcites Falsig et al., 2008
• Not checked yetcites Shah et al., 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Pais et al., 2008

In the paper

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

What the sources say

• Not checked yetcites Kielian et al., 2005

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Galarneau et al., 2007

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Kaur et al., 2004

In the paper

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

What the sources say

• Not checked yetcites Wu et al., 2010

In the paper

“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).”

What the sources say

• Not checked yetcites Faustino et al., 2011

In the paper

“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).”

What the sources say

• Not checked yetcites Hirt et al., 2000
• Not checked yetcites Hirt and Leist, 2003

In the paper

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

What the sources say

• Not checked yetcites Salman et al., 1999

In the paper

“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)”

What the sources say

• Not checked yetcites Chang et al., 2000
• Not checked yetcites Kulprathipanja and Kruse, 2004

In the paper

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

What the sources say

• Not checked yetcites Farfara et al., 2011

In the paper

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

What the sources say

• Not checked yetcites Voisin et al., 2010

In the paper

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

What the sources say

• Not checked yetcites Gitik et al., 2011

In the paper

“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).”

What the sources say

• Not checked yetcites Hirata and Kawabuchi, 2002

In the paper

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

What the sources say

• Not checked yetcites Scott et al., 1993

In the paper

“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).”

What the sources say

• Not checked yetcites Paresce et al., 1996
• Not checked yetcites Liu et al., 2012
• Not checked yetcites Liu et al., 2005

In the paper

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

What the sources say

• Not checked yetcites Tanaka et al., 2009

In the paper

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

What the sources say

• Not checked yetcites Tanaka et al., 2009

In the paper

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

What the sources say

• Not checked yetcites Simard et al., 2006

In the paper

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

What the sources say

• Not checked yetcites Meyer-Luehmann et al., 2008

In the paper

“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).”

What the sources say

• Not checked yetcites Fry et al., 2007

In the paper

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

What the sources say

• Not checked yetcites Wang et al., 2002

In the paper

“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)”

What the sources say

• Not checked yetcites Meyer-Luehmann et al., 2008

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Banati et al., 1993

In the paper

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

What the sources say

• Not checked yetcites Hussain et al., 2006

In the paper

“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).”

What the sources say

• Not checked yetcites Lee et al., 2010; Liu et al., 2010
• Not checked yetcites Fuhrmann et al., 2010

In the paper

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

What the sources say

• Not checked yetcites Gaudet et al. (2011)

In the paper

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

What the sources say

• Not checked yetcites Lai and McLaurin, 2012

In the paper

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

What the sources say

• Not checked yetcites Stalder et al., 2001

In the paper

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

What the sources say

• Not checked yetcites Huang et al., 2010

In the paper

“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.”

What the sources say

• Not checked yetcites Herber et al., 2004
• Not checked yetcites Qiao et al., 2001

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Wang et al., 2002

In the paper

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

What the sources say

• Not checked yetcites Bogie et al., 2011

In the paper

“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).”

What the sources say

• Not checked yetcites Gaudet et al., 2011

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites Smith, 2001

In the paper

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

What the sources say

• Not checked yetcites Gaudet et al., 2011

In the paper

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

What the sources say

• Not checked yetcites Buss et al., 2004

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites Olah et al., 2012