Microglia are multifunctional immune cells in the central nervous system (CNS). In the neurodegenerative diseases such as Alzheimer's disease (AD), accumulation of glial cells, gliosis, occurs in the lesions. The role of accumulated microglia in the pathophysiology of AD is still controversial. When neuronal damage occurs, microglia exert diversified functions, including migration, phagocytosis, and production of various cytokines and chemokines. Among these, microglial phagocytosis of unwanted neuronal debris is critical to maintain the healthy neuronal networks. Microglia express many surface receptors implicated in phagocytosis. It has been suggested that the lack of microglial phagocytosis worsens pathology of AD and induces memory impairment. The present paper summarizes recent evidences on implication of microglial chemotaxis and phagocytosis in AD pathology and discusses the mechanisms related to chemotaxis toward injured neurons and phagocytosis of unnecessary debris. 1. Introduction Microglia are macrophage-like resident immune cells in the central nervous system (CNS) and possess both neurotoxic and neuroprotective function. Microglia accumulate in the lesions of a variety of neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease, and multiple sclerosis, and are thought to play both toxic and protective functions for neuronal survival [1]. Microglia are considered to be a first line defense and respond quickly to various stimuli. When activated, microglia undergo morphological changes to ameboid, proliferate, migrate toward injured areas, and release many soluble factors and phagocytosis of foreign substances or unwanted self-debris. Appropriate migration of microglia to damaged area is controlled by chemokines and nucleotide ATP [2, 3]. Phagocytosis seems to be important to prevent the senile plaque expansion in AD by removing amyloid β (Aβ) deposit [4]. Microglia not only engulf the Aβ protein but also phagocytose apoptotic cells and degenerated neuronal debris. Phagocytosis of apoptotic or degenerated neuronal debris is crucial to reduce inflammation and maintain healthy neuronal networks. Another type of phagocytosis, phagocytosis with inflammation, occurs in chronic inflammatory-related neurodegenerative disorders including Alzheimer disease [5–7]. Degenerated neurons releases several signaling molecules, including nucleotides, cytokines, and chemokines, to recruit microglia and enhance their activities [8, 9]. The phenomenon are now termed as find-me, eat-me, and help-me signals. In this paper, we focused on
References
[1]
D. Farfara, V. Lifshitz, and D. Frenkel, “Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease,” Journal of Cellular and Molecular Medicine, vol. 12, no. 3, pp. 762–780, 2008.
[2]
S. Honda, Y. Sasaki, K. Ohsawa et al., “Extracellular ATP or ADP induce chemotaxis of cultured microglia through -coupled P2Y receptors,” Journal of Neuroscience, vol. 21, no. 6, pp. 1975–1982, 2001.
[3]
J. El Khoury and A. D. Luster, “Mechanisms of microglia accumulation in Alzheimer's disease: therapeutic implications,” Trends in Pharmacological Sciences, vol. 29, no. 12, pp. 626–632, 2008.
[4]
F. Bard, C. Cannon, R. Barbour et al., “Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease,” Nature Medicine, vol. 6, no. 8, pp. 916–919, 2000.
[5]
J. J. Hoarau, P. Krejbich-Trotot, M. C. Jaffar-Bandjee et al., “Activation and control of CNS innate immune responses in health and diseases: a balancing act finely tuned by neuroimmune regulators (NIReg),” CNS & neurological disorders drug targets, vol. 10, no. 1, pp. 25–43, 2011.
[6]
A. D. Fuller and L. J. van Eldik, “MFG-E8 regulates microglial phagocytosis of apoptotic neurons,” Journal of Neuroimmune Pharmacology, vol. 3, no. 4, pp. 246–256, 2008.
[7]
S. McArthur, E. Cristante, M. Paterno et al., “Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia,” Journal of Immunology, vol. 185, no. 10, pp. 6317–6328, 2010.
[8]
S. Koizumi, Y. Shigemoto-Mogami, K. Nasu-Tada et al., “UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis,” Nature, vol. 446, no. 7139, pp. 1091–1095, 2007.
[9]
K. Biber, H. Neumann, K. Inoue, and H. W. G. M. Boddeke, “Neuronal ‘On’ and ‘Off’ signals control microglia,” Trends in Neurosciences, vol. 30, no. 11, pp. 596–602, 2007.
[10]
D. R. Green and H. M. Beere, “Apoptosis: gone but not forgotten,” Nature, vol. 405, no. 6782, pp. 28–29, 2000.
[11]
G. R. Sambrano and D. Steinberg, “Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 5, pp. 1396–1400, 1995.
[12]
R. J. Horvath and J. A. DeLeo, “Morphine enhances microglial migration through modulation of P2X4 receptor signaling,” Journal of Neuroscience, vol. 29, no. 4, pp. 998–1005, 2009.
[13]
Y. Liu, S. Walter, M. Stagi et al., “LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide,” Brain, vol. 128, pp. 1778–1789, 2005.
[14]
A. Stolzing and T. Grune, “Neuronal apoptotic bodies: phagocytosis and degradation by primary microglial cells,” The FASEB journal, vol. 18, no. 6, pp. 743–745, 2004.
[15]
G. E. Landreth and E. G. Reed-Geaghan, “Toll-like receptors in Alzheimer's disease,” Current Topics in Microbiology and Immunology, vol. 336, no. 1, pp. 137–153, 2009.
[16]
A. E. Cardona, E. P. Pioro, M. E. Sasse et al., “Control of microglial neurotoxicity by the fractalkine receptor,” Nature Neuroscience, vol. 9, no. 7, pp. 917–924, 2006.
[17]
S. Lee, N. H. Varvel, M. E. Konerth et al., “CX3CR1 deficiency alters microglial activation and reduces β-amyloid deposition in two Alzheimer's disease mouse models,” American Journal of Pathology, vol. 177, no. 5, pp. 2549–2562, 2010.
[18]
T. Mizuno, Y. Doi, H. Mizoguchi, et al., “Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-β neurotoxicity,” The American Journal of Pathology, vol. 179, no. 4, pp. 2016–2027, 2011.
[19]
U. K. Hanisch, “Microglia as a source and target of cytokines,” Glia, vol. 40, no. 2, pp. 140–155, 2002.
[20]
K. M. Lucin and T. Wyss-Coray, “Immune activation in brain aging and neurodegeneration: too much or too little?” Neuron, vol. 64, no. 1, pp. 110–122, 2009.
[21]
U. K. Hanisch and H. Kettenmann, “Microglia: active sensor and versatile effector cells in the normal and pathologic brain,” Nature Neuroscience, vol. 10, no. 11, pp. 1387–1394, 2007.
[22]
L. Cartier, O. Hartley, M. Dubois-Dauphin, and K. H. Krause, “Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases,” Brain Research Reviews, vol. 48, no. 1, pp. 16–42, 2005.
[23]
J. B. El Khoury, K. J. Moore, T. K. Means et al., “CD36 mediates the innate host response to β-amyloid,” Journal of Experimental Medicine, vol. 197, no. 12, pp. 1657–1666, 2003.
[24]
G. Naert and S. Rivest, “CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease,” Journal of Neuroscience, vol. 31, no. 16, pp. 6208–6220, 2011.
[25]
C. Savarin-Vuaillat and R. M. Ransohoff, “Chemokines and chemokine receptors in neurological disease: raise, retain, or reduce?” Neurotherapeutics, vol. 4, no. 4, pp. 590–601, 2007.
[26]
E. K. de Jong, J. Vinet, V. S. Stanulovic et al., “Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles,” The FASEB Journal, vol. 22, no. 12, pp. 4136–4145, 2008.
[27]
E. K. de Jong, I. M. Dijkstra, M. Hensens et al., “Vesicle-mediated transport and release of CCL21 in endangered neurons: a possible explanation for microglia activation remote from a primary lesion,” Journal of Neuroscience, vol. 25, no. 33, pp. 7548–7557, 2005.
[28]
A. Rappert, K. Biber, C. Nolte et al., “Secondary lymphoid tissue chemokine (CCL21) activates CXCR3 to trigger a Cl- current and chemotaxis in murine microglia,” Journal of Immunology, vol. 168, no. 7, pp. 3221–3226, 2002.
[29]
A. Rappert, I. Bechmann, T. Pivneva et al., “CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion,” Journal of Neuroscience, vol. 24, no. 39, pp. 8500–8509, 2004.
[30]
J. Vinet, E. K. de Jong, H. W. G. M. Boddeke et al., “Expression of CXCL10 in cultured cortical neurons,” Journal of Neurochemistry, vol. 112, no. 3, pp. 703–714, 2010.
[31]
I. M. Dijkstra, S. Hulshof, P. van der Valk, H. W. G. M. Boddeke, and K. Biber, “Cutting edge: activity of human adult microglia in response to CC chemokine ligand 21,” Journal of Immunology, vol. 172, no. 5, pp. 2744–2747, 2004.
[32]
K. Biber, M. Tsuda, H. Tozaki-Saitoh et al., “Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development,” The EMBO Journal, vol. 30, no. 9, pp. 1864–1873, 2011.
[33]
S. Sorce, R. Myburgh, and K. H. Krause, “The chemokine receptor CCR5 in the central nervous system,” Progress in Neurobiology, vol. 93, no. 2, pp. 297–311, 2011.
[34]
S. Sorce, J. Bonnefont, S. Julien et al., “Increased brain damage after ischaemic stroke in mice lacking the chemokine receptor CCR5,” British Journal of Pharmacology, vol. 160, no. 2, pp. 311–321, 2010.
[35]
J. M. Crain, M. Nikodemova, and J. J. Watters, “Expression of P2 nucleotide receptors varies with age and sex in murine brain microglia,” Journal of Neuroinflammation, vol. 6, article no. 1742, p. 24, 2009.
[36]
J. M. Sanz, P. Chiozzi, D. Ferrari et al., “Activation of microglia by amyloid β requires P2X7 receptor expression,” Journal of Immunology, vol. 182, no. 7, pp. 4378–4385, 2009.
[37]
S. E. Haynes, G. Hollopeter, G. Yang et al., “The P2Y12 receptor regulates microglial activation by extracellular nucleotides,” Nature Neuroscience, vol. 9, no. 12, pp. 1512–1519, 2006.
[38]
K. Inoue, S. Koizumi, A. Kataoka, H. Tozaki-Saitoh, and M. Tsuda, “Chapter 12 P2Y6-evoked microglial phagocytosis,” International Review of Neurobiology, vol. 85, pp. 159–163, 2009.
[39]
Y. Pan, C. Lloyd, H. Zhou et al., “Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation,” Nature, vol. 387, no. 6633, pp. 611–617, 1997.
[40]
A. Nishiyori, M. Minami, Y. Ohtani et al., “Localization of fractalkine and CX3CR1 mRNAs in rat brain: does fractalkine play a role in signaling from neuron to microglia?” The FEBS Letters, vol. 429, no. 2, pp. 167–172, 1998.
[41]
J. K. Harrison, Y. Jiang, S. Chen et al., “Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 18, pp. 10896–10901, 1998.
[42]
T. Mizuno, J. Kawanokuchi, K. Numata, and A. Suzumura, “Production and neuroprotective functions of fractalkine in the central nervous system,” Brain Research, vol. 979, no. 1-2, pp. 65–70, 2003.
[43]
K. Hatori, A. Nagai, R. Heisel, J. K. Ryu, and S. U. Kim, “Fractalkine and fractalkine receptors in human neurons and glial cells,” Journal of Neuroscience Research, vol. 69, no. 3, pp. 418–426, 2002.
[44]
S. A. Boehme, F. M. Lio, D. Maciejewski-Lenoir, K. B. Bacon, and P. J. Conlon, “The chemokine fractalkine inhibits Fas-mediated cell death of brain microglia,” Journal of Immunology, vol. 165, no. 1, pp. 397–403, 2000.
[45]
C. Lauro, S. D. Angelantonio, R. Cipriani et al., “Activity of adenosine receptors type 1 is required for CX3CL1-mediated neuroprotection and neuromodulation in hippocampal neurons,” Journal of Immunology, vol. 180, no. 11, pp. 7590–7596, 2008.
[46]
M. Noda, Y. Doi, J. Liang et al., “Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression,” Journal of Biological Chemistry, vol. 286, no. 3, pp. 2308–2319, 2011.
[47]
V. Zujovic, J. Benavides, X. Vige, et al., “Fractalkine modulates TNF-α secretion and neurotoxicity induced by microglial activation,” Glia, vol. 29, no. 4, pp. 305–315, 2000.
[48]
K. J. Garton, P. J. Gough, C. P. Blobel et al., “Tumor necrosis factor-α-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1),” Journal of Biological Chemistry, vol. 276, no. 41, pp. 37993–38001, 2001.
[49]
C. Hundhausen, D. Misztela, T. A. Berkhout et al., “The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion,” Blood, vol. 102, no. 4, pp. 1186–1195, 2003.
[50]
C. L. Tsou, C. A. Haskell, and I. F. Charo, “Tumor necrosis factor-α-converting enzyme mediates the inducible cleavage of fractalkine,” Journal of Biological Chemistry, vol. 276, no. 48, pp. 44622–44626, 2001.
[51]
A. K. Clark, P. K. Yip, J. Grist et al., “Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 25, pp. 10655–10660, 2007.
[52]
G. A. Chapman, K. Moores, D. Harrison, C. A. Campbell, B. R. Stewart, and P. J. Strijbos, “Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage,” Journal of Neuroscience, vol. 20, no. 15, p. RC87, 2000.
[53]
F. Fahrenholz, “α-secretase as a therapeutic target,” Current Alzheimer Research, vol. 4, no. 4, pp. 412–417, 2007.
[54]
R. Postina, A. Schroeder, I. Dewachter et al., “A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model,” Journal of Clinical Investigation, vol. 113, no. 10, pp. 1456–1464, 2004.
[55]
E. A. Milward, R. Papadopoulos, S. J. Fuller et al., “The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth,” Neuron, vol. 9, no. 1, pp. 129–137, 1992.
[56]
L. W. Jin, H. Ninomiya, J. M. Roch et al., “Peptides containing the RERMS sequence of amyloid β/A4 protein precursor bind cell surface and promote neurite extension,” Journal of Neuroscience, vol. 14, no. 9, pp. 5461–5470, 1994.
[57]
J. Walter, C. Kaether, H. Steiner, and C. Haass, “The cell biology of Alzheimer's disease: uncovering the secrets of secretases,” Current Opinion in Neurobiology, vol. 11, no. 5, pp. 585–590, 2001.
[58]
R. E. Tanzi and L. Bertram, “Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective,” Cell, vol. 120, no. 4, pp. 545–555, 2005.
[59]
S. R. Green, K. H. Han, Y. Chen et al., “The CC chemokine MCP-1 stimulates surface expression of CX3CR1 and enhances the adhesion of monocytes to fractalkine/CX3CL1 via p38 MAPK,” Journal of Immunology, vol. 176, no. 12, pp. 7412–7420, 2006.
[60]
M. M. Pabon, A. D. Bachstetter, C. E. Hudson, C. Gemma, and P. C. Bickford, “CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease,” Journal of Neuroinflammation, vol. 8, article 9, 2011.
[61]
M. Fuhrmann, T. Bittner, C. K. E. Jung et al., “Microglial CX3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease,” Nature Neuroscience, vol. 13, no. 4, pp. 411–413, 2010.
[62]
H. Neumann, M. R. Kotter, and R. J. M. Franklin, “Debris clearance by microglia: an essential link between degeneration and regeneration,” Brain, vol. 132, pp. 288–295, 2009.
[63]
F. Reichert and S. Rotshenker, “Complement-receptor-3 and scavenger-receptor-AI/II mediated myelin phagocytosis in microglia and macrophages,” Neurobiology of Disease, vol. 12, no. 1, pp. 65–72, 2003.
[64]
S. Rotshenker, “Microglia and macrophage activation and the regulation of complement-receptor-3 (CR3/MAC-1)-mediated myelin phagocytosis in injury and disease,” Journal of Molecular Neuroscience, vol. 21, no. 1, pp. 65–72, 2003.
[65]
C. Kaur, H. F. Too, and E. A. Ling, “Phagocytosis of Escherichia coli by amoeboid microglial cells in the developing brain,” Acta Neuropathologica, vol. 107, no. 3, pp. 204–208, 2004.
[66]
J. Husemann, J. D. Loike, R. Anankov, M. Febbraio, and S. C. Silverstein, “Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system,” Glia, vol. 40, no. 2, pp. 195–205, 2002.
[67]
R. A. Schlegel, S. Krahling, M. K. Callahan, and P. Williamson, “CD14 is a component of multiple recognition systems used by macrophages to phagocytose apoptotic lymphocytes,” Cell Death and Differentiation, vol. 6, no. 6, pp. 583–592, 1999.
[68]
A. Devitt, S. Pierce, C. Oldreive, W. H. Shingler, and C. D. Gregory, “CD14-dependent clearance of apoptotic cells by human macrophages: the role of phosphatidylserine,” Cell Death and Differentiation, vol. 10, no. 3, pp. 371–382, 2003.
[69]
E. G. Reed-Geaghan, Q. W. Reed, P. E. Cramer, and G. E. Landreth, “Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu,” Journal of Neuroscience, vol. 30, no. 46, pp. 15369–15373, 2010.
[70]
J. Koenigsknecht and G. Landreth, “Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism,” Journal of Neuroscience, vol. 24, no. 44, pp. 9838–9846, 2004.
[71]
M. E. Bamberger, M. E. Harris, D. R. McDonald, J. Husemann, and G. E. Landreth, “A cell surface receptor complex for fibrillar β-amyloid mediates microglial activation,” Journal of Neuroscience, vol. 23, no. 7, pp. 2665–2674, 2003.
[72]
D. A. Persaud-Sawin, L. Banach, and G. J. Harry, “Raft aggregation with specific receptor recruitment is required for microglial phagocytosis of Aβ42,” Glia, vol. 57, no. 3, pp. 320–335, 2009.
[73]
K. J. Moore, J. El Khoury, L. A. Medeiros et al., “A CD36-initiated signaling cascade mediates inflammatory effects of β-amyloid,” Journal of Biological Chemistry, vol. 277, no. 49, pp. 47373–47379, 2002.
[74]
A. Kharitonenkov, Z. Chen, I. Sures, H. Wang, J. Schilling, and A. Ullrich, “A family of proteins that inhibit signalling through tyrosine kinase receptors,” Nature, vol. 386, no. 6621, pp. 181–186, 1997.
[75]
T. Matozaki, Y. Murata, H. Okazawa, and H. Ohnishi, “Functions and molecular mechanisms of the CD47-SIRPα signalling pathway,” Trends in Cell Biology, vol. 19, no. 2, pp. 72–80, 2009.
[76]
M. Gitik, S. Liraz-Zaltsman, P. A. Oldenborg, F. Reichert, and S. Rotshenker, “Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPα (signal regulatory protein-α) on phagocytes,” Journal of Neuroinflammation, vol. 8, article 24, 2011.
[77]
P. A. Oldenborg, A. Zheleznyak, Y. F. Fang, C. F. Lagenaur, H. D. Gresham, and F. P. Lindberg, “Role of CD47 as a marker of self on red blood cells,” Science, vol. 288, no. 5473, pp. 2051–2054, 2000.
[78]
S. D. Yan, X. Chen, J. Fu et al., “RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease,” Nature, vol. 382, no. 6593, pp. 685–691, 1996.
[79]
S. D. Yan, H. Zhu, J. Fu et al., “Amyloid-β peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 10, pp. 5296–5301, 1997.
[80]
A. Friggeri, S. Banerjee, S. Biswas et al., “Participation of the receptor for advanced glycation end products in efferocytosis,” Journal of Immunology, vol. 186, no. 11, pp. 6191–6198, 2011.
[81]
S. Dukic-Stefanovic, J. Gasic-Milenkovic, W. Deuther-Conrad, and G. Münch, “Signal transduction pathways in mouse microglia N-11 cells activated by advanced glycation endproducts (AGEs),” Journal of Neurochemistry, vol. 87, no. 1, pp. 44–55, 2003.
[82]
R. Kang, D. Tang, N. E. Schapiro et al., “The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival,” Cell Death and Differentiation, vol. 17, no. 4, pp. 666–676, 2010.
[83]
R. Dearie, A. Sagare, and B. V. Zlokovic, “The role of the cell surface LRP and soluble LRP in blood-brain barrier Aβ clearance in Alzheimer's disease,” Current Pharmaceutical Design, vol. 14, no. 16, pp. 1601–1605, 2008.
[84]
N. Koning, D. F. Swaab, R. M. Hoek, and I. Huitinga, “Distribution of the immune inhibitory molecules CD200 and CD200R in the normal central nervous system and multiple sclerosis lesions suggests neuron-glia and glia-glia interactions,” Journal of Neuropathology and Experimental Neurology, vol. 68, no. 2, pp. 159–167, 2009.
[85]
H. Matsumoto, Y. Kumon, H. Watanabe et al., “Expression of CD200 by macrophage-like cells in ischemic core of rat brain after transient middle cerebral artery occlusion,” Neuroscience Letters, vol. 418, no. 1, pp. 44–48, 2007.
[86]
D. A. Carter and A. D. Dick, “CD200 maintains microglial potential to migrate in adult human retinal explant model,” Current Eye Research, vol. 28, no. 6, pp. 427–436, 2004.
[87]
T. Langmann, “Microglia activation in retinal degeneration,” Journal of Leukocyte Biology, vol. 81, no. 6, pp. 1345–1351, 2007.
[88]
S. Zhang, X. J. Wang, L. P. Tian, et al., “CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease,” Journal of Neuroinflammation, vol. 8, no. 1, p. 154, 2011.
[89]
D. G. Walker, J. E. Dalsing-Hernandez, N. A. Campbell, and L. F. Lue, “Decreased expression of CD200 and CD200 receptor in Alzheimer's disease: a potential mechanism leading to chronic inflammation,” Experimental Neurology, vol. 215, no. 1, pp. 5–19, 2009.
[90]
K. Takahashi, C. D. P. Rochford, and H. Neumann, “Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2,” Journal of Experimental Medicine, vol. 201, no. 4, pp. 647–657, 2005.
[91]
G. Sessa, P. Podini, M. Mariani et al., “Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia,” European Journal of Neuroscience, vol. 20, no. 10, pp. 2617–2628, 2004.
[92]
K. Takahashi, M. Prinz, M. Stagi, O. Chechneva, and H. Neumann, “TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis,” PLoS Medicine, vol. 4, no. 4, p. e124, 2007.
[93]
L. Stefano, G. Racchetti, F. Bianco et al., “The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor,” Journal of Neurochemistry, vol. 110, no. 1, pp. 284–294, 2009.
[94]
B. Melchior, A. E. Garcia, B. K. Hsiung et al., “Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: Implications for vaccine-based therapies for Alzheimer's disease,” ASN Neuro, vol. 2, no. 3, Article ID e00037, 2010.
[95]
B. B. Mishra, U. M. Gundra, and J. M. Teale, “Expression and distribution of Toll-like receptors 11–13 in the brain during murine neurocysticercosis,” Journal of Neuroinflammation, vol. 5, article 53, 2008.
[96]
Z. Shi, Z. Cai, A. Sanchez et al., “A novel toll-like receptor that recognizes vesicular stomatitis virus,” Journal of Biological Chemistry, vol. 286, no. 6, pp. 4517–4524, 2011.
[97]
C. Han, J. Jin, S. Xu, H. Liu, N. Li, and X. Cao, “Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b,” Nature Immunology, vol. 11, no. 8, pp. 734–742, 2010.
[98]
S. Ribes, S. Ebert, T. Regen et al., “Toll-like receptor stimulation enhances phagocytosis and intracellular killing of nonencapsulated and encapsulated Streptococcus pneumoniae by murine microglia,” Infection and Immunity, vol. 78, no. 2, pp. 865–871, 2010.
[99]
M. Song, J. Jin, J. E. Lim et al., “TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease,” Journal of Neuroinflammation, vol. 8, p. 92, 2011.
[100]
S. Ribes, N. Adam, S. Ebert et al., “The viral TLR3 agonist poly(I:C) stimulates phagocytosis and intracellular killing of Escherichia coli by microglial cells,” Neuroscience Letters, vol. 482, no. 1, pp. 17–20, 2010.
[101]
E. G. Reed-Geaghan, J. C. Savage, A. G. Hise, and G. E. Landreth, “CD14 and toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation,” Journal of Neuroscience, vol. 29, no. 38, pp. 11982–11992, 2009.
[102]
D. A. Costello, A. Lyons, S. Denieffe, et al., “Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice: a role for Toll-like receptor activation,” The Journal of Biological Chemistry, vol. 286, no. 40, pp. 34722–34732, 2011.
[103]
C. R. Stewart, L. M. Stuart, K. Wilkinson et al., “CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer,” Nature Immunology, vol. 11, no. 2, pp. 155–161, 2010.
[104]
A. H. Dalpke, M. K. Schafer, M. Frey, et al., “Immunostimulatory CpG-DNA activates murine microglia,” The Journal of Immunology, vol. 168, no. 10, pp. 4854–4863, 2002.
[105]
Y. Doi, T. Mizuno, Y. Maki et al., “Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid β neurotoxicity in in vitro and in vivo models of Alzheimer's disease,” American Journal of Pathology, vol. 175, no. 5, pp. 2121–2132, 2009.
[106]
C. Ravindran, Y. C. Cheng, and S. M. Liang, “CpG-ODNs induces up-regulated expression of chemokine CCL9 in mouse macrophages and microglia,” Cellular Immunology, vol. 260, no. 2, pp. 113–118, 2010.
[107]
R. Hanayama, M. Tanaka, K. Miwa, A. Shinohara, A. Iwamatsu, and S. Nagata, “Identification of a factor that links apoptotic cells to phagocytes,” Nature, vol. 417, no. 6885, pp. 182–187, 2002.
[108]
M. Miyanishi, K. Tada, M. Koike, Y. Uchiyama, T. Kitamura, and S. Nagata, “Identification of Tim4 as a phosphatidylserine receptor,” Nature, vol. 450, no. 7168, pp. 435–439, 2007.
[109]
F. Leonardi-Essmann, M. Emig, Y. Kitamura, R. Spanagel, and P. J. Gebicke-Haerter, “Fractalkine-upregulated milk-fat globule EGF factor-8 protein in cultured rat microglia,” Journal of Neuroimmunology, vol. 160, no. 1-2, pp. 92–101, 2005.
[110]
M. Miksa, D. Amin, R. Wu, W. Dong, T. S. Ravikumar, and P. Wang, “Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages,” Molecular Medicine, vol. 13, no. 11-12, pp. 553–560, 2007.
[111]
S. Akakura, S. Singh, M. Spataro et al., “The opsonin MFG-E8 is a ligand for the αvβ5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells,” Experimental Cell Research, vol. 292, no. 2, pp. 403–416, 2004.
[112]
A. Friggeri, Y. Yang, S. Banerjee, Y. J. Park, G. Liu, and E. Abraham, “HMGB1 inhibits macrophage activity in efferocytosis through binding to the αvβ3-integrin,” American Journal of Physiology, vol. 299, no. 6, pp. C1267–C1276, 2010.
[113]
J. Boddaert, K. Kinugawa, J. C. Lambert et al., “Evidence of a role for lactadherin in Alzheimer's disease,” American Journal of Pathology, vol. 170, no. 3, pp. 921–929, 2007.
[114]
D. Feng, W. L. Zhao, Y. Y. Ye et al., “Cellular internalization of exosomes occurs through phagocytosis,” Traffic, vol. 11, no. 5, pp. 675–687, 2010.
[115]
J. Martinez, J. Almendinger, A. Oberst, et al., “Microtubule-associated protein 1 light chain 3 α (LC3)-associated phagocytosis is required for the efficient clearance of dead cells,” Proceedings of the National Academy of Sciences of the United States, vol. 108, no. 42, pp. 17396–17401, 2011.
[116]
Y. Yamanishi, J. Kitaura, K. Izawa et al., “TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury,” Journal of Experimental Medicine, vol. 207, no. 7, pp. 1501–1511, 2010.
[117]
D. Farfara, D. Trudler, N. Segev-Amzaleg, R. Galron, R. Stein, and D. Frenkel, “γ-secretase component presenilin is important for microglia β-amyloid clearance,” Annals of Neurology, vol. 69, no. 1, pp. 170–180, 2011.
[118]
S. Jayadev, A. Case, A. J. Eastman et al., “Presenilin 2 is the predominant γ-secretase in microglia and modulates cytokine release,” PLoS One, vol. 5, no. 12, Article ID e15743, 2010.
[119]
Y. Nadler, A. Alexandrovich, N. Grigoriadis et al., “Increased expression of the γ-secretase components presenilin-1 and nicastrin in activated astrocytes and microglia following traumatic brain injury,” Glia, vol. 56, no. 5, pp. 552–567, 2008.
[120]
M. He, H. Kubo, K. Morimoto et al., “Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells,” The EMBO Reports, vol. 12, no. 4, pp. 358–364, 2011.
[121]
S. E. Hickman, E. K. Allison, and J. El Khoury, “Microglial dysfunction and defective β-amyloid clearance pathways in aging alzheimer's disease mice,” Journal of Neuroscience, vol. 28, no. 33, pp. 8354–8360, 2008.
