Phagocytic Clearance in Neurodegeneration
2011; Elsevier BV; Volume: 178; Issue: 4 Linguagem: Inglês
10.1016/j.ajpath.2010.12.051
ISSN1525-2191
AutoresJennifer D. Sokolowski, James W. Mandell,
Tópico(s)Neuroscience and Neuropharmacology Research
ResumoThe cellular and molecular mechanisms of phagocytic clearance of apoptotic cells and debris have been intensely studied in invertebrate model organisms and in the mammalian immune system. This evolutionarily conserved process serves multiple purposes. Uncleared debris from dying cells or aggregated proteins can be toxic and may trigger exaggerated inflammatory responses. Even though apoptotic cell death and debris accumulation are key features of neurodegenerative diseases, relatively little attention has been paid to this important homeostatic function in the central nervous system (CNS). This review attempts to summarize our knowledge of phagocytic clearance in the CNS, with a focus on retinal degeneration, forms of which are caused by mutations in genes within known phagocytic pathways, and on Alzheimer's disease (AD). Interest in phagocytic clearance mechanisms in AD was stimulated by the discovery that immunization could promote phagocytic clearance of amyloid-β; however, much less is known about clearance of neuronal and synaptic corpses in AD and other neurodegenerative diseases. Because the regulation of phagocytic activity is intertwined with cytokine signaling, this review also addresses the relationships among CNS inflammation, glial responses, and phagocytic clearance. The cellular and molecular mechanisms of phagocytic clearance of apoptotic cells and debris have been intensely studied in invertebrate model organisms and in the mammalian immune system. This evolutionarily conserved process serves multiple purposes. Uncleared debris from dying cells or aggregated proteins can be toxic and may trigger exaggerated inflammatory responses. Even though apoptotic cell death and debris accumulation are key features of neurodegenerative diseases, relatively little attention has been paid to this important homeostatic function in the central nervous system (CNS). This review attempts to summarize our knowledge of phagocytic clearance in the CNS, with a focus on retinal degeneration, forms of which are caused by mutations in genes within known phagocytic pathways, and on Alzheimer's disease (AD). Interest in phagocytic clearance mechanisms in AD was stimulated by the discovery that immunization could promote phagocytic clearance of amyloid-β; however, much less is known about clearance of neuronal and synaptic corpses in AD and other neurodegenerative diseases. Because the regulation of phagocytic activity is intertwined with cytokine signaling, this review also addresses the relationships among CNS inflammation, glial responses, and phagocytic clearance. Two decades of work in both Caenorhabditis elegans and Drosophila melanogaster models, as well as in mammalian non-neural cells, has revealed numerous receptors and intracellular effector molecules involved in the recognition and engulfment of apoptotic cells (Figure 1).1Elliott M.R. Ravichandran K.S. Clearance of apoptotic cells: implications in health and disease.J Cell Biol. 2010; 189: 1059-1070Crossref PubMed Scopus (392) Google Scholar However, to what extent and in which cell types these molecules function in the context of specific neurodegenerative diseases is largely unstudied. Although infiltrating macrophages and their CNS-resident counterparts, microglia, are considered the professional phagocytes in the brain, there are other populations of potential phagocytes in the CNS, including astrocytes, neural stem cells, and possibly even neurons. These cell types derive from different lineages, exhibit different characteristics, and are likely to have distinct roles in phagocytic clearance. Microglia derive from the hematopoietic lineage, and express typical pattern recognition receptors, including the Toll-like receptors, Fc and complement receptors, cytokine receptors, CD40 and MHC molecules (Table 1). Microglia perform typical immune cell functions, including phagocytosis and antigen presentation, as well as production of inflammatory mediators and modulation of the general immune response.2Lee C.Y. Landreth G.E. The role of microglia in amyloid clearance from the AD brain.J Neural Transm. 2010; 117: 949-960Crossref PubMed Scopus (439) Google Scholar Microglia are well known for clearing dead and dying neurons after injury and therefore are a prime candidate for playing a role in phagocytic clearance in neurodegeneration.Table 1Expression of Potential Phagocytic Receptors in Central Nervous System CellsReceptorLigandRelevanceExpression detectedReferencesMicrogliaAstrocytesNeuronsPhosphatidylserine receptors BAI1PSUptake of apoptotic cells×××1Elliott M.R. Ravichandran K.S. Clearance of apoptotic cells: implications in health and disease.J Cell Biol. 2010; 189: 1059-1070Crossref PubMed Scopus (392) Google Scholar TIM4PSUptake of apoptotic cells1Elliott M.R. Ravichandran K.S. Clearance of apoptotic cells: implications in health and disease.J Cell Biol. 2010; 189: 1059-1070Crossref PubMed Scopus (392) Google Scholar Scavenger family receptorsPSUptake of apoptotic cells1Elliott M.R. Ravichandran K.S. Clearance of apoptotic cells: implications in health and disease.J Cell Biol. 2010; 189: 1059-1070Crossref PubMed Scopus (392) Google Scholar, 89Kinchen J.M. Ravichandran K.S. Journey to the grave: signaling events regulating removal of apoptotic cells.J Cell Sci. 2007; 120: 2143-2149Crossref PubMed Scopus (91) Google ScholarOpsonin receptors MerTKGas6 (binds PS)Uptake of POS, apoptotic cells××3Cahoy J.D. Emery B. Kaushal A. Foo L.C. Zamanian J.L. Christopherson K.S. Xing Y. Lubischer J.L. Krieg P.A. Krupenko S.A. Thompson W.J. Barres B.A. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function.J Neurosci. 2008; 28: 264-278Crossref PubMed Scopus (2229) Google Scholar, 26Hall M.O. Prieto A.L. Obin M.S. Abrams T.A. Burgess B.L. Heeb M.J. Agnew B.J. Outer segment phagocytosis by cultured retinal pigment epithelial cells requires Gas6.Exp Eye Res. 2001; 73: 509-520Crossref PubMed Scopus (73) Google ScholarGas 6 production⁎Asterisk indicates that the ligand is an opsonin (bridging molecule), rather than the direct target of the phagocytic receptor.×× αvβ3/5 integrinMfge8 (binds PS)Uptake of apoptotic cells, uptake of Aβ×××3Cahoy J.D. Emery B. Kaushal A. Foo L.C. Zamanian J.L. Christopherson K.S. Xing Y. Lubischer J.L. Krieg P.A. Krupenko S.A. Thompson W.J. Barres B.A. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function.J Neurosci. 2008; 28: 264-278Crossref PubMed Scopus (2229) Google Scholar, 79Boddaert J. Kinugawa K. Lambert J.C. Boukhtouche F. Zoll J. Merval R. Blanc-Brude O. Mann D. Berr C. Vilar J. Garabedian B. Journiac N. Charue D. Silvestre J.S. Duyckaerts C. Amouyel P. Mariani J. Tedgui A. Mallat Z. 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Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells.Am J Pathol. 2007; 171: 1989-1999Abstract Full Text Full Text PDF PubMed Scopus (111) Google ScholarApoE production⁎Asterisk indicates that the ligand is an opsonin (bridging molecule), rather than the direct target of the phagocytic receptor.× LRP1ApoEUptake of Aβ-ApoE complexes, BBB-associated Aβ receptor××3Cahoy J.D. Emery B. Kaushal A. Foo L.C. Zamanian J.L. Christopherson K.S. Xing Y. Lubischer J.L. Krieg P.A. Krupenko S.A. Thompson W.J. Barres B.A. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function.J Neurosci. 2008; 28: 264-278Crossref PubMed Scopus (2229) Google Scholar, 95Wilhelmus M.M. Otte-Höller I. van Triel J.J. Veerhuis R. Maat-Schieman M.L. Bu G. de Waal R.M. Verbeek M.M. Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells.Am J Pathol. 2007; 171: 1989-1999Abstract Full Text Full Text PDF PubMed Scopus (111) Google ScholarUptake of Aβ-ApoJ complexes× LRP2/megalinClusterin (ApoJ)Clusterin production⁎Asterisk indicates that the ligand is an opsonin (bridging molecule), rather than the direct target of the phagocytic receptor.×××55Barnum S.R. Complement biosynthesis in the central nervous system.Crit Rev Oral Biol Med. 1995; 6: 132-146Crossref PubMed Scopus (163) Google Scholar, 75Nuutinen T. Suuronen T. Kauppinen A. Salminen A. Clusterin: a forgotten player in Alzheimer's disease.Brain Res Rev. 2009; 61: 89-104Crossref PubMed Scopus (223) Google Scholar, 95Wilhelmus M.M. Otte-Höller I. van Triel J.J. Veerhuis R. Maat-Schieman M.L. Bu G. de Waal R.M. Verbeek M.M. Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells.Am J Pathol. 2007; 171: 1989-1999Abstract Full Text Full Text PDF PubMed Scopus (111) Google ScholarAβ, amyloid-β; Apo, apolipoprotein; BAI1, brain-specific angiogenesis inhibitor-1; BBB, blood-brain barrier; FcR, Fc receptor; FPRL1, formyl peptide receptor-like 1; Gas6, growth-arrest specific 6; LDLR, low density lipoprotein receptor; LRP, low density lipoprotein receptor-related; MerTK, Mer receptor tyrosine kinase; Mfge8, milk fat globule-EGF factor 8 (also known as lactadherin); POS, photoreceptor outer segments; PS, phosphatidylserine; RAGE, receptor for advanced glycation endproducts; TIM4, T-cell immunoglobulin and mucin-domain-containing molecule 4; TLR, Toll-like receptor. Asterisk indicates that the ligand is an opsonin (bridging molecule), rather than the direct target of the phagocytic receptor. Open table in a new tab Aβ, amyloid-β; Apo, apolipoprotein; BAI1, brain-specific angiogenesis inhibitor-1; BBB, blood-brain barrier; FcR, Fc receptor; FPRL1, formyl peptide receptor-like 1; Gas6, growth-arrest specific 6; LDLR, low density lipoprotein receptor; LRP, low density lipoprotein receptor-related; MerTK, Mer receptor tyrosine kinase; Mfge8, milk fat globule-EGF factor 8 (also known as lactadherin); POS, photoreceptor outer segments; PS, phosphatidylserine; RAGE, receptor for advanced glycation endproducts; TIM4, T-cell immunoglobulin and mucin-domain-containing molecule 4; TLR, Toll-like receptor. Astrocytes originate from neural stem cells, sharing common precursors with oligodendrocytes and neurons. A recent microarray study on acutely isolated mouse brain astrocytes unexpectedly revealed that these cells express many components of evolutionarily conserved phagocytic pathways and numerous receptors involved in innate immunity, including Toll-like receptors, scavenger receptors, and mannose receptors, as well as components of the complement system (Table 1).3Cahoy J.D. Emery B. Kaushal A. Foo L.C. Zamanian J.L. Christopherson K.S. Xing Y. Lubischer J.L. Krieg P.A. Krupenko S.A. Thompson W.J. Barres B.A. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function.J Neurosci. 2008; 28: 264-278Crossref PubMed Scopus (2229) Google Scholar Activation of these receptors prompts not only phagocytosis, but also production of cytokines that lead to amplification and/or suppression of the immune response.4DeWitt D.A. Perry G. Cohen M. Doller C. Silver J. Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease.Exp Neurol. 1998; 149: 329-340Crossref PubMed Scopus (219) Google Scholar A few studies suggest that even neurons are capable of engulfment, although in many cases the phenomenon is probably better characterized as endocytosis or pinocytosis. Neurons and neuronal cell lines are able to take up aggregated extracellular amyloid-β (Aβ) in vitro, and both low-density lipoprotein receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) have been implicated in this process5Takuma K. Fang F. Zhang W. Yan S. Fukuzaki E. Du H. Sosunov A. McKhann G. Funatsu Y. Nakamichi N. Nagai T. Mizoguchi H. Ibi D. Hori O. Ogawa S. Stern D.M. Yamada K. Yan S.S. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction.Proc Natl Acad Sci USA. 2009; 106: 20021-20026Crossref PubMed Scopus (238) Google Scholar, 6Hu X. Crick S.L. Bu G. Frieden C. 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Degenerating synaptic boutons in prion disease: microglia activation without synaptic stripping.Am J Pathol. 2009; 175: 1610-1621Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Whether neurons actually completely phagocytose and process the degenerating material is not clear. Although neurons express at least some of the relevant receptors and intracellular engulfment machinery (Table 1), signaling through these receptors may have different downstream effects than in immune cells, with expression of adaptor proteins and coreceptors that are specific to neurons.9van Noort J.M. Bsibsi M. Toll-like receptors in the CNS: implications for neurodegeneration and repair.Prog Brain Res. 2009; 175: 139-148Crossref PubMed Scopus (97) Google Scholar Although microglia are considered by some to be the macrophages of the brain, it has been suggested that peripherally derived macrophages have different properties than resident microglia and could contribute to clearance of Aβ plaques.10Simard A.R. Soulet D. Gowing G. Julien J.P. Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease.Neuron. 2006; 49: 489-502Abstract Full Text Full Text PDF PubMed Scopus (979) Google Scholar This has been difficult to study, however. When peripheral monocytes incorporate into the parenchyma, it is usually impossible to distinguish them from resident microglia morphologically, because there are no specific markers that definitively differentiate them. In addition, there is debate about whether peripheral monocytes infiltrate into the parenchyma to a significant degree under nontraumatic circumstances.11Tsuchiya T. Park K.C. Toyonaga S. Yamada S.M. Nakabayashi H. Nakai E. Ikawa N. Furuya M. Tominaga A. Shimizu K. Characterization of microglia induced from mouse embryonic stem cells and their migration into the brain parenchyma.J Neuroimmunol. 2005; 160: 210-218Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 12Mildner A. Schmidt H. Nitsche M. Merkler D. Hanisch U.K. Mack M. Heikenwalder M. Bruck W. Priller J. Prinz M. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions.Nat Neurosci. 2007; 10: 1544-1553Crossref PubMed Scopus (812) Google Scholar Some studies using bone marrow transplant with green fluorescent protein-expressing myeloid cells suggest that, in Alzheimer's disease models, monocytes are recruited to the brain, evolve morphologically and functionally into microglia, and localize to sites of Aβ deposition. Critics of this theory, however, have shown that the irradiation involved in bone marrow transplantation increases the leakiness of the blood-brain barrier and that the previous model has not unequivocally demonstrated that infiltration occurs to a significant degree without radiation.12Mildner A. Schmidt H. Nitsche M. Merkler D. Hanisch U.K. Mack M. Heikenwalder M. Bruck W. Priller J. Prinz M. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions.Nat Neurosci. 2007; 10: 1544-1553Crossref PubMed Scopus (812) Google Scholar Activation of a glial cell in response to debris not only stimulates phagocytosis, but also results in other downstream effects, such as secretion of cytokines and production of reactive oxygen species.13Fraser D.A. Pisalyaput K. Tenner A.J. C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production.J Neurochem. 2010; 112: 733-743Crossref PubMed Scopus (136) Google Scholar An issue that complicates analysis of the literature is that researchers refer to activation of glia without acknowledging or accounting for the ambiguity of that label. This is problematic, because there is a continuum of activation for microglia that entails a range of phenotypes, and the expression of activation markers can vary.14Morgan D. Gordon M.N. Tan J. Wilcock D. Rojiani A.M. Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics.J Neuropathol Exp Neurol. 2005; 64: 743-753Crossref PubMed Scopus (164) Google Scholar For example, activation markers such as p38, CD45, and FcR have been shown to be differentially regulated over time in amyloid precursor protein (APP) transgenic mice exposed to anti-Aβ immunotherapy.14Morgan D. Gordon M.N. Tan J. Wilcock D. Rojiani A.M. Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics.J Neuropathol Exp Neurol. 2005; 64: 743-753Crossref PubMed Scopus (164) Google Scholar Using one marker is clearly insufficient to fully characterize the activation phenotype of a glial cell. Macrophage activation has been described in terms of classical (M1) and alternative (M2) activation, largely based on cytokine and receptor expression profiles.15Michelucci A. Heurtaux T. Grandbarbe L. Morga E. Heuschling P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-beta.J Neuroimmunol. 2009; 210: 3-12Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar Classical activation has as a hallmark the production of pro-inflammatory cytokines and free radicals; alternative activation is a less well defined anti-inflammatory phenotype. Expression profiling offers some utility, and use of delineations that have been established for macrophages serves as a starting point. Nonetheless, the immunomodulatory milieu in the CNS differs, and activation phenotypes in the CNS may not mimic those in the periphery.16Carson M.J. Sutcliffe J.G. Balancing function vs. self defense: the CNS as an active regulator of immune responses.J Neurosci Res. 1999; 55: 1-8Crossref PubMed Scopus (88) Google Scholar Quantitative real-time PCR examining expression of genes associated with inflammation indicated that, in AD brain and in AD mouse models, innate immune cells exhibit a hybrid activation state characteristic of both classical and alternative activation.17Colton C.A. Mott R.T. Sharpe H. Xu Q. Van Nostrand W.E. Vitek M.P. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD.J Neuroinflammation. 2006; 3: 27Crossref PubMed Scopus (338) Google Scholar Further studies are needed to generate functional delineations, so that researchers can better categorize the spectrum of glial activation phenotypes. Cell-cell interactions and the cytokine environment determine whether phagocytes are ready for clearance. Several studies have shown that astrocytes modulate microglial phagocytic activity in vitro.4DeWitt D.A. Perry G. Cohen M. Doller C. Silver J. Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease.Exp Neurol. 1998; 149: 329-340Crossref PubMed Scopus (219) Google Scholar, 18Town T. Nikolic V. Tan J. The microglial “activation” continuum: from innate to adaptive responses.J Neuroinflammation. 2005; 2: 24Crossref PubMed Scopus (353) Google Scholar Astrocyte-conditioned medium has a general inhibitory effect,4DeWitt D.A. Perry G. Cohen M. Doller C. Silver J. Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease.Exp Neurol. 1998; 149: 329-340Crossref PubMed Scopus (219) Google Scholar and a relatively unexplored concept is that interactions of CD40 and CD40 ligand (CD40L) could be involved.19Calingasan N.Y. Erdely H.A. Altar C.A. Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury.Neurobiol Aging. 2002; 23: 31-39Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar CD40-CD40L binding plays a role in peripheral immune activation and results in a range of outcomes, including up-regulation of costimulatory molecules, activation of antigen-presenting cells, and stimulation of cytokine production.18Town T. Nikolic V. Tan J. The microglial “activation” continuum: from innate to adaptive responses.J Neuroinflammation. 2005; 2: 24Crossref PubMed Scopus (353) Google Scholar Neuronal signals also appear to influence the activation of glia. For example, in culture, neuronal activity modulates interferon-γ-induced major histocompatibility complex class II (MHCII) expression on astrocytes and microglia, ultimately dampening inflammatory activity.20Biber K. Neumann H. Inoue K. Boddeke H.W. Neuronal ‘On’ and ‘Off’ signals control microglia.Trends Neurosci. 2007; 30: 596-602Abstract Full Text Full Text PDF PubMed Scopus (586) Google Scholar Thus, it seems likely that neurons influence the overall activation phenotype and phagocytic properties of surrounding glia. In the context of neurodegeneration, neurons may lose their ability to dampen glial proinflammatory activity. T cells are able to modulate microglial activities in vitro, and studies have shown that Treg cells can be neuroprotective.21Reynolds A.D. Banerjee R. Liu J. Gendelman H.E. Mosley R.L. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson's disease.J Leukoc Biol. 2007; 82: 1083-1094Crossref PubMed Scopus (276) Google Scholar Although T cells have the machinery for direct communication (eg, through CD40-CD40L interactions), their relatively limited access to CNS parenchyma implies that indirect mechanisms such as cytokine signaling could be involved. Further work is needed to evaluate the complex integration of proinflammatory and anti-inflammatory cytokine signaling in glial cells and their combined effects on phagocytic activity.22Koenigsknecht-Talboo J. Landreth G.E. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines.J Neurosci. 2005; 25: 8240-8249Crossref PubMed Scopus (380) Google Scholar, 23Yamamoto M. Kiyota T. Walsh S.M. Liu J. Kipnis J. Ikezu T. Cytokine-mediated inhibition of fibrillar amyloid-beta peptide degradation by human mononuclear phagocytes.J Immunol. 2008; 181: 3877-3886PubMed Google Scholar Even though one of the key features of neurodegeneration is cell death and synapse loss, we know little about the ultimate fate of cell corpses and debris in disease states. Growing evidence implicates autophagy as a key process in several neurodegenerative diseases.24Kohli L. Roth K.A. Autophagy: cerebral home cooking.Am J Pathol. 2010; 176: 1065-1071Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar In theory, however, a neuron undergoing autophagic death must still ultimately be cleared by phagocytosis. Although culture studies have convi
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