Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain

Abbas N, Bednar I, Mix E, Marie S, Paterson D, Ljungberg A, Morris C, Winblad B, Nordberg A, Zhu J (2002) Up-regulation of the inflammatory cytokines IFN-gamma and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APP(SWE) transgenic mice. J Neuroimmunol 126:50–57

Abbott NJ (2004) Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 45:545–552

Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53

Adams DO, Hamilton TA (1987) Molecular transductional mechanisms by which IFN gamma and other signals regulate macrophage development. Immunol Rev 97:5–27

Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543

Andrews AL, Holloway JW, Holgate ST, Davies DE (2006) IL-4 receptor alpha is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets. J Immunol 176:7456–7461

Atochina O, Da’dara AA, Walker M, Harn DA (2008) The immunomodulatory glycan LNFPIII initiates alternative activation of murine macrophages in vivo. Immunology 125:111–121

Baetz A, Frey M, Heeg K, Dalpke AH (2004) Suppressor of cytokine signaling (SOCS) proteins indirectly regulate toll-like receptor signaling in innate immune cells. J Biol Chem 279:54708–54715

Basu A, Krady JK, Enterline JR, Levison SW (2002) Transforming growth factor beta1 prevents IL-1beta-induced microglial activation, whereas TNF alpha- and IL-6-stimulated activation are not antagonized. Glia 40:109–120

Bharadwaj PR, Dubey AK, Masters CL, Martins RN, Macreadie IG (2009) Abeta aggregation and possible implications in Alzheimer’s disease pathogenesis. J Cell Mol Med 13(3):412–421

Birge RB, Ucker DS (2008) Innate apoptotic immunity: the calming touch of death. Cell Death Differ 15:1096–1102

Bogdan C (2008) Mechanisms and consequences of persistence of intracellular pathogens: leishmaniasis as an example. Cell Microbiol 10:1221–1234

Bogdan C, Vodovotz Y, Nathan C (1991) Macrophage deactivation by interleukin 10. J Exp Med 174:1549–1555

Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, Kohsaka S, Jucker M, Calhoun ME (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 28:4283–4292

Boulton M, Young A, Hay J, Armstrong D, Flessner M, Schwartz M, Johnston M (1996) Drainage of CSF through lymphatic pathways and arachnoid villi in sheep: measurement of 125I-albumin clearance. Neuropathol Appl Neurobiol 22:325–333

Boulton M, Flessner M, Armstrong D, Hay J, Johnston M (1998) Determination of volumetric cerebrospinal fluid absorption into extracranial lymphatics in sheep. Am J Physiol 274:R88–R96

Braissant O, Gotoh T, Loup M, Mori M, Bachmann C (1999) l-arginine uptake, the citrulline–NO cycle and arginase II in the rat brain: an in situ hybridization study. Brain Res Mol Brain Res 70:231–241

Brodie C, Goldreich N, Haiman T, Kazimirsky G (1998) Functional IL-4 receptors on mouse astrocytes: IL-4 inhibits astrocyte activation and induces NGF secretion. J Neuroimmunol 81:20–30

Buga GM, Singh R, Pervin S, Rogers NE, Schmitz DA, Jenkinson CP, Cederbaum SD, Ignarro LJ (1996) Arginase activity in endothelial cells: inhibition by NG-hydroxy-l-arginine during high-output NO production. Am J Physiol 271:H1988–H1998

Busch SA, Silver J (2007) The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol 17:120–127

Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, Weller RO (2008) Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol 34:131–144

Castellani RJ, Siedlak SL, Fortino AE, Perry G, Ghetti B, Smith MA (2005) Chitin-like polysaccharides in Alzheimer's disease brains. Curr Alzheimer Res 2:419–423

Cederbaum SD, Yu H, Grody WW, Kern RM, Yoo P, Iyer RK (2004) Arginases I and II: do their functions overlap? Mol Genet Metab 81(Suppl 1):S38–S44

Chieppa M, Bianchi G, Doni A, Del Prete A, Sironi M, Laskarin G, Monti P, Piemonti L, Biondi A, Mantovani A, Introna M, Allavena P (2003) Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program. J Immunol 171:4552–4560

Chuang TH, Ulevitch RJ (2004) Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors. Nat Immunol 5:495–502

Closs EI, Boissel JP, Habermeier A, Rotmann A (2006) Structure and function of cationic amino acid transporters (CATs). J Membr Biol 213:67–77

Colton C, Wilt S, Gilbert D, Chernyshev O, Snell J, Dubois-Dalcq M (1996) Species differences in the generation of reactive oxygen species by microglia. Mol Chem Neuropathol 28:15–20

Colton CA, Chernyshev ON, Gilbert DL, Vitek MP (2000) Microglial contribution to oxidative stress in Alzheimer’s disease. Ann N Y Acad Sci 899:292–307

Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP (2006a) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3:27

Colton CA, Vitek MP, Wink DA, Xu Q, Cantillana V, Previti ML, Van Nostrand WE, Weinberg JB, Dawson H (2006b) NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 103:12867–12872

Conde JR, Streit WJ (2006) Microglia in the aging brain. J Neuropathol Exp Neurol 65:199–203

Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180:5771–5777

Crocker PR, Paulson JC, Varki A (2007) Siglecs and their roles in the immune system. Nat Rev Immunol 7:255–266

Cunningham C, Boche D, Perry VH (2002) Transforming growth factor beta1, the dominant cytokine in murine prion disease: influence on inflammatory cytokine synthesis and alteration of vascular extracellular matrix. Neuropathol Appl Neurobiol 28:107–119

Czapiga M, Colton CA (2003) Microglial function in human APOE3 and APOE4 transgenic mice: altered arginine transport. J Neuroimmunol 134:44–51

De Simone R, Ajmone-Cat MA, Minghetti L (2004) Atypical anti-inflammatory activation of microglia induced by apoptotic neurons: possible role of phosphatidylserine–phosphatidylserine receptor interaction. Mol Neurobiol 29:197–212

Denker SP, Ji S, Dingman A, Lee SY, Derugin N, Wendland MF, Vexler ZS (2007) Macrophages are comprised of resident brain microglia not infiltrating peripheral monocytes acutely after neonatal stroke. J Neurochem 100:893–904

Durante W, Liao L, Reyna SV, Peyton KJ, Schafer AI (2001) Transforming growth factor-beta(1) stimulates L-arginine transport and metabolism in vascular smooth muscle cells: role in polyamine and collagen synthesis. Circulation 103:1121–1127

Ebert S, Schoeberl T, Walczak Y, Stoecker K, Stempfl T, Moehle C, Weber BH, Langmann T (2008) Chondroitin sulfate disaccharide stimulates microglia to adopt a novel regulatory phenotype. J Leukoc Biol 84:736–740

Edwards JP, Zhang X, Frauwirth KA, Mosser DM (2006) Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 80:1298–1307

Erwig LP, Henson PM (2007) Immunological consequences of apoptotic cell phagocytosis. Am J Pathol 171:2–8

Fabriek BO, Dijkstra CD, van den Berg TK (2005) The macrophage scavenger receptor CD163. Immunobiology 210:153–160

Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101:890–898

Finch CE, Laping NJ, Morgan TE, Nichols NR, Pasinetti GM (1993) TGF-beta 1 is an organizer of responses to neurodegeneration. J Cell Biochem 53:314–322

Ford JW, Kilmon MA, Haas KM, Shelburne AE, Chan-Li Y, Conrad DH (2006) In vivo murine CD23 destabilization enhances CD23 shedding and IgE synthesis. Cell Immunol 243:107–117

Freire-de-Lima CG, Xiao YQ, Gardai SJ, Bratton DL, Schiemann WP, Henson PM (2006) Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J Biol Chem 281:38376–38384

Fuller AD, Van Eldik L (2008) MFG-E8 regulates microglial phagocytosis of apoptotic neurons. J Neuroimmune Pharmacol 3:246–256

Galea I, Palin K, Newman TA, Van Rooijen N, Perry VH, Boche D (2005) Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain. Glia 49:375–384

Galtrey CM, Fawcett JW (2007) The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res Rev 54:1–18

Ganster RW, Taylor BS, Shao L, Geller DA (2001) Complex regulation of human inducible nitric oxide synthase gene transcription by Stat 1 and NF-kappa B. Proc Natl Acad Sci U S A 98:8638–8643

Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, Bratton DL, Oldenborg PA, Michalak M, Henson PM (2005) Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321–334

Garlind A, Brauner A, Hojeberg B, Basun H, Schultzberg M (1999) Soluble interleukin-1 receptor type II levels are elevated in cerebrospinal fluid in Alzheimer’s disease patients. Brain Res 826:112–116

Glezer I, Simard AR, Rivest S (2007) Neuroprotective role of the innate immune system by microglia. Neuroscience 147:867–883

Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35

Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964

Gratchev A, Kzhyshkowska J, Utikal J, Goerdt S (2005) Interleukin-4 and dexamethasone counterregulate extracellular matrix remodelling and phagocytosis in type-2 macrophages. Scand J Immunol 61:10–17

Gratchev A, Kzhyshkowska J, Kothe K, Muller-Molinet I, Kannookadan S, Utikal J, Goerdt S (2006) Mphi1 and Mphi2 can be re-polarized by Th2 or Th1 cytokines, respectively, and respond to exogenous danger signals. Immunobiology 211:473–486

Gregory CD, Devitt A (2004) The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically? Immunology 113:1–14

Griffiths MR, Gasque P, Neal JW (2009) The multiple roles of the innate immune system in the regulation of apoptosis and inflammation in the brain. J Neuropathol Exp Neurol 68:217–226

Grommes C, Lee CY, Wilkinson BL, Jiang Q, Koenigsknecht-Talboo JL, Varnum B, Landreth GE (2008) Regulation of microglial phagocytosis and inflammatory gene expression by Gas6 acting on the Axl/Mer family of tyrosine kinases. J Neuroimmune Pharmacol 3:130–140

Hamerman JA, Lanier LL (2006) Inhibition of immune responses by ITAM-bearing receptors. Sci STKE 2006:re1

Hamilton TA, Ohmori Y, Tebo JM, Kishore R (1999) Regulation of macrophage gene expression by pro- and anti-inflammatory cytokines. Pathobiology 67:241–244

Han J, Ulevitch RJ (2005) Limiting inflammatory responses during activation of innate immunity. Nat Immunol 6:1198–1205

Herber DL, Mercer M, Roth LM, Symmonds K, Maloney J, Wilson N, Freeman MJ, Morgan D, Gordon MN (2007) Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. J Neuroimmune Pharmacol 2:222–231

Hughes JE, Srinivasan S, Lynch KR, Proia RL, Ferdek P, Hedrick CC (2008) Sphingosine-1-phosphate induces an anti inflammatory phenotype in macrophages. Circ Res 102:950–958

Hume DA (2008) Bring out your dead. Nat Immunol 9:12–14

Hung SI, Chang AC, Kato I, Chang NC (2002) Transient expression of Ym1, a heparin-binding lectin, during developmental hematopoiesis and inflammation. J Leukoc Biol 72:72–82

Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, Ruano D, Vizuete M, Gutierrez A, Vitorica J (2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 28:11650–11661

Junker N, Johansen JS, Hansen LT, Lund EL, Kristjansen PE (2005) Regulation of YKL-40 expression during genotoxic or microenvironmental stress in human glioblastoma cells. Cancer Sci 96:183–190

Kariko K, Weissman D, Welsh FA (2004) Inhibition of toll-like receptor and cytokine signaling—a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab 24:1288–1304

Kawakami M, Leland P, Kawakami K, Puri RK (2001) Mutation and functional analysis of IL-13 receptors in human malignant glioma cells. Oncol Res 12:459–467

Kerrigan AM, Brown GD (2009) C-type lectins and phagocytosis. Immunobiology 214:562–575

Kiefer R, Streit WJ, Toyka KV, Kreutzberg GW, Hartung HP (1995) Transforming growth factor-beta 1: a lesion-associated cytokine of the nervous system. Int J Dev Neurosci 13:331–339

Kitamura Y, Taniguchi T, Kimura H, Nomura Y, Gebicke-Haerter PJ (2000) Interleukin-4-inhibited mRNA expression in mixed rat glial and in isolated microglial cultures. J Neuroimmunol 106:95–104

Kuhn PH, Marjaux E, Imhof A, De Strooper B, Haass C, Lichtenthaler SF (2007) Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase. J Biol Chem 282:11982–11995

Lang R, Patel D, Morris JJ, Rutschman RL, Murray PJ (2002) Shaping gene expression in activated and resting primary macrophages by IL-10. J Immunol 169:2253–2263

Ledeboer A, Breve JJ, Poole S, Tilders FJ, Van Dam AM (2000) Interleukin-10, interleukin-4, and transforming growth factor-beta differentially regulate lipopolysaccharide-induced production of pro-inflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells. Glia 30:134–142

Lee TS, Chau LY (2002) Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med 8:240–246

Lee YB, Nagai A, Kim SU (2002) Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res 69:94–103

Leidi M, Gotti E, Bologna L, Miranda E, Rimoldi M, Sica A, Roncalli M, Palumbo GA, Introna M, Golay J (2009) M2 macrophages phagocytose rituximab-opsonized leukemic targets more efficiently than m1 cells in vitro. J Immunol 182:4415–4422

Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357

Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146

Linehan SA, Martinez-Pomares L, Stahl PD, Gordon S (1999) Mannose receptor and its putative ligands in normal murine lymphoid and nonlymphoid organs: in situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular microglia, and mesangial cells, but not dendritic cells. J Exp Med 189:1961–1972

Linehan SA, Coulson PS, Wilson RA, Mountford AP, Brombacher F, Martinez-Pomares L, Gordon S (2003) IL-4 receptor signaling is required for mannose receptor expression by macrophages recruited to granulomata but not resident cells in mice infected with Schistosoma mansoni. Lab Invest 83:1223–1231

Liu J, Hatzoglou M (1998) Control of expression of the gene for the arginine transporter Cat-1 in rat liver cells by glucocorticoids and insulin. Amino Acids 15:321–337

Liu T, Dhanasekaran SM, Jin H, Hu B, Tomlins SA, Chinnaiyan AM, Phan SH (2004) FIZZ1 stimulation of myofibroblast differentiation. Am J Pathol 164:1315–1326

Lodge PA, Sriram S (1996) Regulation of microglial activation by TGF-beta, IL-10, and CSF-1. J Leukoc Biol 60:502–508

Long EO (2008) Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 224:70–84

Lyons A, Griffin RJ, Costelloe CE, Clarke RM, Lynch MA (2007a) IL-4 attenuates the neuroinflammation induced by amyloid-beta in vivo and in vitro. J Neurochem 101:771–781

Lyons A, Downer EJ, Crotty S, Nolan YM, Mills KH, Lynch MA (2007b) CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J Neurosci 27:8309–8313

Maceyka M, Payne SG, Milstien S, Spiegel S (2002) Sphingosine kinase, sphingosine-1-phosphate, and apoptosis. Biochim Biophys Acta 1585:193–201

Maderna P, Godson C (2003) Phagocytosis of apoptotic cells and the resolution of inflammation. Biochim Biophys Acta 1639:141–151

Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA (2008) Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 28:6333–6341

Makwana M, Jones LL, Cuthill D, Heuer H, Bohatschek M, Hristova M, Friedrichsen S, Ormsby I, Bueringer D, Koppius A, Bauer K, Doetschman T, Raivich G (2007) Endogenous transforming growth factor beta 1 suppresses inflammation and promotes survival in adult CNS. J Neurosci 27:11201–11213

Malaterre J, Strambi C, Aouane A, Strambi A, Rougon G, Cayre M (2004) A novel role for polyamines in adult neurogenesis in rodent brain. Eur J NeuroSci 20:317–330

Manner CK, Nicholson B, MacLeod CL (2003) CAT2 arginine transporter deficiency significantly reduces iNOS-mediated NO production in astrocytes. J Neurochem 85:476–482

Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555

Marletta MA (1994) Nitric oxide synthase: aspects concerning structure and catalysis. Cell 78:927–930

Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461

Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738

Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724

Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10:1544–1553

Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164:6166–6173

Minghetti L, Pocchiari M (2007) Cyclooxygenase-2, prostaglandin E2, and microglial activation in prion diseases. Int Rev Neurobiol 82:265–275

Minghetti L, Ajmone-Cat MA, De Berardinis MA, De Simone R (2005) Microglial activation in chronic neurodegenerative diseases: roles of apoptotic neurons and chronic stimulation. Brain Res Brain Res Rev 48:251–256

Moncada S, Higgs EA (1991) Endogenous nitric oxide: physiology, pathology and clinical relevance. Eur J Clin Invest 21:361–374

Morgan TE, Nichols NR, Pasinetti GM, Finch CE (1993) TGF-beta 1 mRNA increases in macrophage/microglial cells of the hippocampus in response to deafferentation and kainic acid-induced neurodegeneration. Exp Neurol 120:291–301

Morris SM Jr (2004a) Recent advances in arginine metabolism. Curr Opin Clin Nutr Metab Care 7:45–51

Morris SM Jr (2004b) Enzymes of arginine metabolism. J Nutr 134:2743S–2747S discussion 2765S–2767S

Morris SM Jr (2007) Arginine metabolism: boundaries of our knowledge. J Nutr 137:1602S–1609S

Morris SM Jr, Kepka-Lenhart D, Chen LC (1998) Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells. Am J Physiol 275:E740–E747

Morwood SR, Nicholson LB (2006) Modulation of the immune response by extracellular matrix proteins. Arch Immunol Ther Exp (Warsz) 54:367–374

Mosser DM (2003) The many faces of macrophage activation. J Leukoc Biol 73:209–212

Mosser DM, Zhang X (2008) Interleukin-10: new perspectives on an old cytokine. Immunol Rev 226:205–218

Nimmerjahn F, Ravetch JV (2006) Fcgamma receptors: old friends and new family members. Immunity 24:19–28

Noel W, Raes G, Hassanzadeh Ghassabeh G, De Baetselier P, Beschin A (2004) Alternatively activated macrophages during parasite infections. Trends Parasitol 20:126–133

O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007) MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A 104:1604–1609

Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Eagle AR, Vats D, Brombacher F, Ferrante AW, Chawla A (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447:1116–1120

Ogawa R, Pacelli R, Espey MG, Miranda KM, Friedman N, Kim SM, Cox G, Mitchell JB, Wink DA, Russo A (2001) Comparison of control of Listeria by nitric oxide redox chemistry from murine macrophages and NO donors: insights into listeriocidal activity of oxidative and nitrosative stress. Free Radic Biol Med 30:268–276

Oshima T, Laroux FS, Coe LL, Morise Z, Kawachi S, Bauer P, Grisham MB, Specian RD, Carter P, Jennings S, Granger DN, Joh T, Alexander JS (2001) Interferon-gamma and interleukin-10 reciprocally regulate endothelial junction integrity and barrier function. Microvasc Res 61:130–143

Pachter JS, de Vries HE, Fabry Z (2003) The blood–brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol 62:593–604

Perry VH, Gordon S (1988) Macrophages and microglia in the nervous system. Trends Neurosci 11:273–277

Perry VH, Cunningham C, Boche D (2002) Atypical inflammation in the central nervous system in prion disease. Curr Opin Neurol 15:349–354

Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161–167

Pfitzner E, Kliem S, Baus D, Litterst CM (2004) The role of STATs in inflammation and inflammatory diseases. Curr Pharm Des 10:2839–2850

Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 27:10714–10721

Pousset F, Cremona S, Dantzer R, Kelley KW, Parnet P (2001) IL-10 and IL-4 regulate type-I and type-II IL-1 receptors expression on IL-1 beta-activated mouse primary astrocytes. J Neurochem 79:726–736

Pratt BM, McPherson JM (1997) TGF-beta in the central nervous system: potential roles in ischemic injury and neurodegenerative diseases. Cytokine Growth Factor Rev 8:267–292

Radde R, Duma C, Goedert M, Jucker M (2008) The value of incomplete mouse models of Alzheimer’s disease. Eur J Nucl Med Mol Imaging 35(Suppl 1):S70–S74

Raes G, Beschin A, Ghassabeh GH, De Baetselier P (2007) Alternatively activated macrophages in protozoan infections. Curr Opin Immunol 19:454–459

Raes G, De Baetselier P, Noel W, Beschin A, Brombacher F, Hassanzadeh Gh G (2002a) Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J Leukoc Biol 71:597–602

Raes G, Noel W, Beschin A, Brys L, de Baetselier P, Hassanzadeh GH (2002b) FIZZ1 and Ym as tools to discriminate between differentially activated macrophages. Dev Immunol 9:151–159

Raes G, Brys L, Dahal BK, Brandt J, Grooten J, Brombacher F, Vanham G, Noel W, Bogaert P, Boonefaes T, Kindt A, Van den Bergh R, Leenen PJ, De Baetselier P, Ghassabeh GH (2005) Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation. J Leukoc Biol 77:321–327

Rajpathak SN, Gunter MJ, Wylie-Rosett J, Ho GY, Kaplan RC, Muzumdar R, Rohan TE, Strickler HD (2009) The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. Diabetes Metab Res Rev 25:3–12

Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F (2009) C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10:514–523

Recklies AD, White C, Ling H (2002) The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways. Biochem J 365:119–126

Reese TA, Liang HE, Tager AM, Luster AD, Van Rooijen N, Voehringer D, Locksley RM (2007) Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447:92–96

Rehli M, Krause SW, Andreesen R (1997) Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation. Genomics 43:221–225

Ren B, Zhang N, Yang J, Ding H (2008) Nitric oxide-induced bacteriostasis and modification of iron–sulphur proteins in Escherichia coli. Mol Microbiol 70:953–964

Ricchetti GA, Williams LM, Foxwell BM (2004) Heme oxygenase 1 expression induced by IL-10 requires STAT-3 and phosphoinositol-3 kinase and is inhibited by lipopolysaccharide. J Leukoc Biol 76:719–726

Ridnour LA, Thomas DD, Mancardi D, Espey MG, Miranda KM, Paolocci N, Feelisch M, Fukuto J, Wink DA (2004) The chemistry of nitrosative stress induced by nitric oxide and reactive nitrogen oxide species. Putting perspective on stressful biological situations. Biol Chem 385:1–10

Ronaldson PT, Demarco KM, Sanchez-Covarrubias L, Solinsky CM, Davis TP (2009) Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood–brain barrier during inflammatory pain. J Cereb Blood Flow Metab 29:1084–1098

Rubartelli A, Lotze MT (2007) Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol 28:429–436

Salimuddin NA, Gotoh T, Isobe H, Mori M (1999) Regulation of the genes for arginase isoforms and related enzymes in mouse macrophages by lipopolysaccharide. Am J Physiol 277:E110–E117

Sandler NG, Mentink-Kane MM, Cheever AW, Wynn TA (2003) Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J Immunol 171:3655–3667

Schaer DJ, Boretti FS, Schoedon G, Schaffner A (2002) Induction of the CD163-dependent haemoglobin uptake by macrophages as a novel anti-inflammatory action of glucocorticoids. Br J Haematol 119:239–243

Schilling M, Besselmann M, Muller M, Strecker JK, Ringelstein EB, Kiefer R (2005) Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 196:290–297

Schwartz M, London A, Shechter R (2009) Boosting T-cell immunity as a therapeutic approach for neurodegenerative conditions: the role of innate immunity. Neuroscience 158:1133–1142

Scotton CJ, Martinez FO, Smelt MJ, Sironi M, Locati M, Mantovani A, Sozzani S (2005) Transcriptional profiling reveals complex regulation of the monocyte IL-1 beta system by IL-13. J Immunol 174:834–845

Serhan CN, Levy B (2003) Novel pathways and endogenous mediators in anti-inflammation and resolution. Chem Immunol Allergy 83:115–145

Shah VB, Huang Y, Keshwara R, Ozment-Skelton T, Williams DL, Keshvara L (2008) Beta-glucan activates microglia without inducing cytokine production in Dectin-1-dependent manner. J Immunol 180:2777–2785

Shimohama S, Tanino H, Kawakami N, Okamura N, Kodama H, Yamaguchi T, Hayakawa T, Nunomura A, Chiba S, Perry G, Smith MA, Fujimoto S (2000) Activation of NADPH oxidase in Alzheimer’s disease brains. Biochem Biophys Res Commun 273:5–9

Shin WH, Lee DY, Park KW, Kim SU, Yang MS, Joe EH, Jin BK (2004) Microglia expressing interleukin-13 undergo cell death and contribute to neuronal survival in vivo. Glia 46:142–152

Snell JC, Chernyshev O, Gilbert DL, Colton CA (1997) Polyribonucleotides induce nitric oxide production by human monocyte-derived macrophages. J Leukoc Biol 62:369–373

Sotgiu S, Musumeci S, Marconi S, Gini B, Bonetti B (2008) Different content of chitin-like polysaccharides in multiple sclerosis and Alzheimer’s disease brains. J Neuroimmunol 197:70–73

Soulet D, Rivest S (2008) Bone-marrow-derived microglia: myth or reality? Curr Opin Pharmacol 8:508–518

Sterka D Jr, Marriott I (2006) Characterization of nucleotide-binding oligomerization domain (NOD) protein expression in primary murine microglia. J Neuroimmunol 179:65–75

Stoeck K, Bodemer M, Ciesielczyk B, Meissner B, Bartl M, Heinemann U, Zerr I (2005) Interleukin 4 and interleukin 10 levels are elevated in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Arch Neurol 62:1591–1594

Streit WJ, Kincaid-Colton CA (1995) The brain’s immune system. Sci Am 273(54–55):58–61

Stutz AM, Pickart LA, Trifilieff A, Baumruker T, Prieschl-Strassmayr E, Woisetschlager M (2003) The Th2 cell cytokines IL-4 and IL-13 regulate found in inflammatory zone 1/resistin-like molecule alpha gene expression by a STAT6 and CCAAT/enhancer-binding protein-dependent mechanism. J Immunol 170:1789–1796

Suzuki Y, Claflin J, Wang X, Lengi A, Kikuchi T (2005) Microglia and macrophages as innate producers of interferon-gamma in the brain following infection with Toxoplasma gondii. Int J Parasitol 35:83–90

Szczepanik AM, Funes S, Petko W, Ringheim GE (2001) IL-4, IL-10 and IL-13 modulate A beta(1–42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol 113:49–62

Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201:647–657

Taketomi T, Hara A, Kasama T (1984) Cerebral and visceral organ gangliosides and related glycolipids in gm1-gangliosidosis type 1, type 2 and chronic type. Adv Exp Med Biol 174:419–429

Tan J, Town T, Mori T, Wu Y, Saxe M, Crawford F, Mullan M (2000) CD45 opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activated protein kinase. J Neurosci 20:7587–7594

Taylor KR, Gallo RL (2006) Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. FASEB J 20:9–22

Taylor PR, Gordon S, Martinez-Pomares L (2005a) The mannose receptor: linking homeostasis and immunity through sugar recognition. Trends Immunol 26:104–110

Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S (2005b) Macrophage receptors and immune recognition. Annu Rev Immunol 23:901–944

Taylor PR, Reid DM, Heinsbroek SE, Brown GD, Gordon S, Wong SY (2005c) Dectin-2 is predominantly myeloid restricted and exhibits unique activation-dependent expression on maturing inflammatory monocytes elicited in vivo. Eur J Immunol 35:2163–2174

Thomas T, Thomas TJ (2001) Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications. Cell Mol Life Sci 58:244–258

Thomas DD, Ridnour LA, Isenberg JS, Flores-Santana W, Switzer CH, Donzelli S, Hussain P, Vecoli C, Paolocci N, Ambs S, Colton CA, Harris CC, Roberts DD, Wink DA (2008) The chemical biology of nitric oxide: implications in cellular signaling. Free Radic Biol Med 45:18–31

Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (2007) CD4 + CD25 + Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A 104:19446–19451

Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B, Fabbri M, Alder H, Liu CG, Calin GA, Croce CM (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179:5082–5089

Townsend KP, Vendrame M, Ehrhart J, Faza B, Zeng J, Town T, Tan J (2004) CD45 isoform RB as a molecular target to oppose lipopolysaccharide-induced microglial activation in mice. Neurosci Lett 362:26–30

Ulevitch RJ, Mathison JC, da Silva Correia J (2004) Innate immune responses during infection. Vaccine 22(Suppl 1):S25–S30

Underhill DM (2007) Collaboration between the innate immune receptors dectin-1, TLRs, and Nods. Immunol Rev 219:75–87

Underhill DM, Goodridge HS (2007) The many faces of ITAMs. Trends Immunol 28:66–73

Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20:515–524

van Lookeren Campagne M, Wiesmann C, Brown EJ (2007) Macrophage complement receptors and pathogen clearance. Cell Microbiol 9:2095–2102

Van Muiswinkel FL, Veerhuis R, Eikelenboom P (1996) Amyloid beta protein primes cultured rat microglial cells for an enhanced phorbol 12-myristate 13-acetate-induced respiratory burst activity. J Neurochem 66:2468–2476

van Rossum D, Hilbert S, Strassenburg S, Hanisch UK, Bruck W (2008) Myelin-phagocytosing macrophages in isolated sciatic and optic nerves reveal a unique reactive phenotype. Glia 56:271–283

Villoslada P, Moreno B, Melero I, Pablos JL, Martino G, Uccelli A, Montalban X, Avila J, Rivest S, Acarin L, Appel S, Khoury SJ, McGeer P, Ferrer I, Delgado M, Obeso J, Schwartz M (2008) Immunotherapy for neurological diseases. Clin Immunol 128:294–305

Vincendeau P, Gobert AP, Daulouede S, Moynet D, Mossalayi MD (2003) Arginases in parasitic diseases. Trends Parasitol 19:9–12

Vivien D, Ali C (2006) Transforming growth factor-beta signalling in brain disorders. Cytokine Growth Factor Rev 17:121–128

Wallace HM, Duff PM, Pearson CK, Keir HM (1981) The effect of polyamines of DNA synthesis in vitro. Biochim Biophys Acta 652:354–357

Wallace HM, Fraser AV, Hughes A (2003) A perspective of polyamine metabolism. Biochem J 376:1–14

Wei R, Jonakait GM (1999) Neurotrophins and the anti-inflammatory agents interleukin-4 (IL-4), IL-10, IL-11 and transforming growth factor-beta1 (TGF-beta1) down-regulate T cell costimulatory molecules B7 and CD40 on cultured rat microglia. J Neuroimmunol 95:8–18

Weinberg JB, Misukonis MA, Shami PJ, Mason SN, Sauls DL, Dittman WA, Wood ER, Smith GK, McDonald B, Bachus KE et al (1995) Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages. Blood 86:1184–1195

Weigert A, Tzieply N, von Knethen A, Johann AM, Schmidt H, Geisslinger G, Brune B (2007) Tumor cell apoptosis polarizes macrophages role of sphingosine-1-phosphate. Mol Biol Cell 18:3810–3819

Weis N, Weigert A, von Knethen A, Brune B (2009) Heme oxygenase-1 contributes to an alternative macrophage activation profile induced by apoptotic cell supernatants. Mol Biol Cell 20:1280–1288

Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18:253–266

Wiesinger H (2001) Arginine metabolism and the synthesis of nitric oxide in the nervous system. Prog Neurobiol 64:365–391

Wilcock DM, Lewis MR, Van Nostrand WE, Davis J, Previti ML, Gharkholonarehe N, Vitek MP, Colton CA (2008) Progression of amyloid pathology to Alzheimer’s disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J Neurosci 28:1537–1545

Wilkinson B, Koenigsknecht-Talboo J, Grommes C, Lee CY, Landreth G (2006) Fibrillar beta-amyloid-stimulated intracellular signaling cascades require Vav for induction of respiratory burst and phagocytosis in monocytes and microglia. J Biol Chem 281:20842–20850

Williams K (1997) Interactions of polyamines with ion channels. Biochem J 325(Pt 2):289–297

Williams K, Dooley N, Ulvestad E, Becher B, Antel JP (1996) IL-10 production by adult human derived microglial cells. Neurochem Int 29:55–64

Williams LM, Sarma U, Willets K, Smallie T, Brennan F, Foxwell BM (2007) Expression of constitutively active STAT3 can replicate the cytokine-suppressive activity of interleukin-10 in human primary macrophages. J Biol Chem 282:6965–6975

Willment JA, Lin HH, Reid DM, Taylor PR, Williams DL, Wong SY, Gordon S, Brown GD (2003) Dectin-1 expression and function are enhanced on alternatively activated and GM-CSF-treated macrophages and are negatively regulated by IL-10, dexamethasone, and lipopolysaccharide. J Immunol 171:4569–4573

Wink DA, Hanbauer I, Krishna MC, DeGraff W, Gamson J, Mitchell JB (1993) Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. Proc Natl Acad Sci U S A 90:9813–9817

Wink DA, Hanbauer I, Grisham MB, Laval F, Nims RW, Laval J, Cook J, Pacelli R, Liebmann J, Krishna M, Ford PC, Mitchell JB (1996) Chemical biology of nitric oxide: regulation and protective and toxic mechanisms. Curr Top Cell Regul 34:159–187

Wink DA, Miranda KM, Espey MG, Pluta RM, Hewett SJ, Colton C, Vitek M, Feelisch M, Grisham MB (2001) Mechanisms of the antioxidant effects of nitric oxide. Antioxid Redox Signal 3:203–213

Wu Y, Tibrewal N, Birge RB (2006) Phosphatidylserine recognition by phagocytes: a view to a kill. Trends Cell Biol 16:189–197

Wu Z, Tokuda Y, Zhang XW, Nakanishi H (2008) Age-dependent responses of glial cells and leptomeninges during systemic inflammation. Neurobiol Dis 32:543–551

Wynn TA, Thompson RW, Cheever AW, Mentink-Kane MM (2004) Immunopathogenesis of schistosomiasis. Immunol Rev 201:156–167

Xiao YQ, Freire-de-Lima CG, Schiemann WP, Bratton DL, Vandivier RW, Henson PM (2008) Transcriptional and translational regulation of TGF-beta production in response to apoptotic cells. J Immunol 181:3575–3585

Yeramian A, Martin L, Arpa L, Bertran J, Soler C, McLeod C, Modolell M, Palacin M, Lloberas J, Celada A (2006a) Macrophages require distinct arginine catabolism and transport systems for proliferation and for activation. Eur J Immunol 36:1516–1526

Yeramian A, Martin L, Serrat N, Arpa L, Soler C, Bertran J, McLeod C, Palacin M, Modolell M, Lloberas J, Celada A (2006b) Arginine transport via cationic amino acid transporter 2 plays a critical regulatory role in classical or alternative activation of macrophages. J Immunol 176:5918–5924

Yu H, Iyer RK, Kern RM, Rodriguez WI, Grody WW, Cederbaum SD (2001) Expression of arginase isozymes in mouse brain. J Neurosci Res 66:406–422

Yu H, Yoo PK, Aguirre CC, Tsoa RW, Kern RM, Grody WW, Cederbaum SD, Iyer RK (2003) Widespread expression of arginase I in mouse tissues. Biochemical and physiological implications. J Histochem Cytochem 51:1151–1160

Zhang G, Ghosh S (2002) Negative regulation of toll-like receptor-mediated signaling by Tollip. J Biol Chem 277:7059–7065

Zhu J, Guo L, Watson CJ, Hu-Li J, Paul WE (2001) Stat6 is necessary and sufficient for IL-4’s role in Th2 differentiation and cell expansion. J Immunol 166:7276–7281

Zocchia C, Spiga G, Rabin SJ, Grekova M, Richert J, Chernyshev O, Colton C, Mocchetti I (1997) Biological activity of interleukin-10 in the central nervous system. Neurochem Int 30:433–439