Cellular and Molecular Life Sciences

, Volume 76, Issue 4, pp 745–755 | Cite as

How toll-like receptors reveal monocyte plasticity: the cutting edge of antiinflammatory therapy

  • Catherine RopertEmail author


Toll-like receptors (TLR)s are central in immune response by recognizing pathogen-associated molecular patterns (PAMP)s. If they are essential to eliminate pathogens in earlier stages of infection, they also might play a role in homeostasis and tissue repair. TLR versatility parallels the plasticity of monocytes, which represent an heterogeneous population of immune cells. They are rapidly recruited to sites of infection and involved in clearance of pathogens and in tissue healing. This review underlines how TLRs have proved to be an interesting tool to study the properties of monocytes and why different therapeutic strategies exploring monocyte plasticity may be relevant in the context of chronic inflammatory disorders.


Monocytes TLR Mal/TIRAP IRAK4 Inflammation 


Compliance with ethical standards

Conflict of interest

The author declares that there is no conflict of interest.


  1. 1.
    Steinman R, Hoffmann J, Beutler B (2011) Editorial: nobel Prize to immunology. Nat Rev Immunol 11:714. Google Scholar
  2. 2.
    O’Neill LAJ, Golenbock D, Bowie AG (2013) The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol 13(6):453–460. Google Scholar
  3. 3.
    Jin MS, Lee JO (2008) Structures of the toll-like receptor family and its ligand complexes. Immunity 29:182–191. Google Scholar
  4. 4.
    Takeuchi O, Akira S (2001) Toll-like receptors; their physiological role and signal transduction system. Int Immunopharmacol 1:625–635. Google Scholar
  5. 5.
    Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820. Google Scholar
  6. 6.
    Ozinsky A et al (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA 97:13766–13771. Google Scholar
  7. 7.
    Trinchieri G, Sher A (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7(3):179–190. Google Scholar
  8. 8.
    Farrar CA et al (2012) Inhibition of TLR2 promotes graft function in a murine model of renal transplant ischemia-reperfusion injury. FASEB J 26:799–807. Google Scholar
  9. 9.
    Geissmann F, Auffray C, Palframan R, Wirrig C, Ciocca A, Campisi L, Narni-Mancinelli E, Lauvau G (2008) Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses. Immunol Cell Biol 86:398–408. Google Scholar
  10. 10.
    Serbina NV, Jia T, Hohl TM, Pamer EG (2008) Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 26:421–452. Google Scholar
  11. 11.
    Auffray C, Sieweke MH, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692. Google Scholar
  12. 12.
    Ingersoll MA, Platt AM, Potteaux S, Randolph GJ (2011) Monocyte trafficking in acute and chronic inflammation. Trends Immunol 32:470–477. Google Scholar
  13. 13.
    Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82. Google Scholar
  14. 14.
    Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, Sarnacki S, Cumano A, Lauvau G, Geissmann F (2007) Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317:666–670. Google Scholar
  15. 15.
    Ingersoll MA et al (2010) Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 115:e10–e19. Google Scholar
  16. 16.
    Ziegler-Heitbrock L, Hofer TP (2013) Toward a refined definition of monocyte subsets. Front Immunol 4(23):1–5. Google Scholar
  17. 17.
    Takeuchi O et al (2001) Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 13:933–940Google Scholar
  18. 18.
    Gazzinelli RT, Denkers EY (2006) Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism. Nat Rev Immunol 6:895–906. Google Scholar
  19. 19.
    Blasius AL, Beutler B (2010) Intracellular toll-like receptors. J Immunol 32(3):305–315. Google Scholar
  20. 20.
    van Bergenhenegouwen J, Plantinga TS, Joosten LAB, Netea MG, Folkerts G, Kraneveld AD, Garssen J, Vos AP (2013) TLR2 & Co: a critical analysis of the complex interactions between TLR2 and coreceptors. J Leuk Biol 94(5):885–902. Google Scholar
  21. 21.
    Lee CC, Avalos AM, Ploegh HL (2012) Accessory molecules for Toll-like receptors and their functions. Nat Rev Immunol 12:168–179. Google Scholar
  22. 22.
    Kawasaki T, Kawai T (2014) Toll-like receptors signaling pathways. Front Immunol 5:461. Google Scholar
  23. 23.
    Flannery S, Bowie AG (2010) The interleukin-1 receptor-associated kinases: critical regulators of innate immune signalling. Biochem Pharmacol 80:1981–1991. Google Scholar
  24. 24.
    Cohen P (2014) The TLR and IL-1 signalling network at a glance. J Cell Sci 127:2383–2390. Google Scholar
  25. 25.
    O’Neill LAJ, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353–364. Google Scholar
  26. 26.
    Deguine J, Barton GM (2014) MyD88: a central player in innate immune signaling. F1000 Prime Re 6:97.
  27. 27.
    Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z (1997) MyD88: an adapter that recruits IRAK to the-1 receptor complex. Immunity 7:837–847. Google Scholar
  28. 28.
    Lin SC, Lo YC, Wu H (2010) Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465(7300):885–890. Google Scholar
  29. 29.
    Kawai T, Akira S (2007) Signaling to NF-kB by Toll-like receptors. Trends Mol Med 13(11):460–469. Google Scholar
  30. 30.
    Kumar H, Kawai T, Akira S (2009) Toll-like receptors and innate immunity. Biochem Biophys Res Com 388(4):621–625. Google Scholar
  31. 31.
    Verstak B, Nagpal K, Bottomley SP, Golenbock DT, Hertzog PJ, Mansell A (2009) MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses. J Biol Chem 284(36):24192–24203. Google Scholar
  32. 32.
    Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol 11:373–384. Google Scholar
  33. 33.
    Mellett M, Atzei P, Jackson R, O’Neill LA, Moynagh PN (2011) Mal mediates TLR-induced activation of CREB and expression of IL-10. J Immunol 186(8):4925–4935. Google Scholar
  34. 34.
    Sanin DE, Prendergast CT, Mountford AP (2015) IL-10 production in macrophages is regulated by a TLR-driven CREB-mediated mechanism that is linked to gene involved in cell metabolism. J Immunol 195(3):1218–1232. Google Scholar
  35. 35.
    Colonna M (2007) TLR pathways and IFN-regulatory factors: to each its own. Eur J Immunol 37(2):306–309. Google Scholar
  36. 36.
    Honda K, Taniguchi T (2006) Toll-like receptor signaling and IRF transcription factors. IUBMB Life 58(5–6):290–295. Google Scholar
  37. 37.
    Horng T, Barton GM, Flavell RA, Medzhitov R (2002) The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420(6913):329–333. Google Scholar
  38. 38.
    Yamamoto M et al (2002) Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420:324–329. Google Scholar
  39. 39.
    Bonham KS, Orzalli MH, Hayashi K, Wolf AI, Glanemann C, Weninger W, Iwasaki A, Knipe DM, Kagan JC (2014) A promiscuous lipid-binding protein diversifies the subcellular sites of Toll-like Receptor signal transduction. Cell 156(4):705–716. Google Scholar
  40. 40.
    Kenny EF, Talbot S, Gong M, Golenbock DT, Bryant CE, O’Neill LA (2009) MyD88 adaptor-like is not essential for TLR2 signaling and inhibits signaling by TLR3. J Immunol 183:3642–3651. Google Scholar
  41. 41.
    Gravina HD, Goes AM, Murta SMF, Ropert C (2016) MyD88 adapter-like (Mal)/TIRAP is required for cytokine pro duction by splenic Ly6CloTLR2hi but not by Ly6ChiTLR2hi monocytes during infection. J Biol Chem 291:23832–23841. Google Scholar
  42. 42.
    Ní Cheallaigh C et al (2016) A common variant in the adaptor mal regulates interferon gamma signaling. Immunity 44:368–379. Google Scholar
  43. 43.
    Kagan JC (2012) Defining the subcellular sites of innate immune signal Transduction. Trends Immunol 33(9):442–448. Google Scholar
  44. 44.
    Kagan JC, Medzhitov R (2006) Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125(5):943–955. Google Scholar
  45. 45.
    Rowe DC, McGettrick AF, Latz E, Monks BG, Gay NJ, Yamamoto M, Akira S, O’Neill LA, Fitzgerald KA, Golenbock DT (2006) The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc Natl Acad Sci USA 103(16):6299–6304. Google Scholar
  46. 46.
    Weiss DS, Raupach B, Takeda K, Akira S, Zychlinsky A (2004) Toll-like receptors are temporally involved in host defense. J Immunol 172:4463–4469. Google Scholar
  47. 47.
    Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A (2005) TLR9 regulates TH1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med 202:1715–1724. Google Scholar
  48. 48.
    Bafica A, Santiago HC, Goldszmid R, Ropert C, Gazzinelli RT, Sher A (2006) Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruzi infection. J Immunol 177:3515–3519. Google Scholar
  49. 49.
    Ropert C, Almeida IC, Closel M, Luiz R, Ferguson MAJ, Cohen P, Gazzinelli T (2001) Requirement of mitogen-activated protein kinases and iκb phosphorylation for induction of proinflammatory cytokines synthesis by macrophages indicates functional similarity of receptors triggered by glycosylphosphatidylinositol anchors from parasitic protozoan. J Immunol 166:3423–3431. Google Scholar
  50. 50.
    Campos MA, Almeida IC, Takeuchi O, Akira S, Valente EP, Procópio DO, Travassos LR, Smith JA, Golenbock DT, Gazzinelli RT (2001) Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J Immunol 167(1):416–423. Google Scholar
  51. 51.
    Bartholomeu DC et al (2008) Recruitment and endo-lysosomal activation of TLR9 in dendritic cells infected with Trypanosoma cruzi. J Immunol 181:1333–1344. Google Scholar
  52. 52.
    Ropert C, Gazzinelli RT (2004) Regulatory role of Toll-like receptor 2 during infection with Trypanosoma cruzi. J Endotoxin Res 10:425–430Google Scholar
  53. 53.
    Gravina HD, Antonelli L, Gazzinelli RT, Ropert C (2013) Differential Use of TLR2 and TLR9 in the Regulation of Immune Responses during the Infection with Trypanosoma cruzi. PLoS One 8(5):e63100. Google Scholar
  54. 54.
    Sato S, Nomura F, Kawai T, Takeuchi O, Mühlradt PF, Takeda K, Akira S (2000) Synergy and cross-tolerance between toll-like receptor (TLR) 2- and TLR4-mediated signaling pathways. J Immunol 165(12):7096–7101. Google Scholar
  55. 55.
    De Nardo D, De Nardo CM, Nguyen T, Hamilton JA, Scholz GM (2009) Signaling crosstalk during sequential TLR4 and TLR9 activation amplifies the inflammatory response of mouse macrophages. J Immunol 183(12):8110–8118. Google Scholar
  56. 56.
    Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A (2005) Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol 6:769–776. Google Scholar
  57. 57.
    Zhu Q, Egelston C, Vivekanandhan A, Uematsu S, Akira S, Klinman DM, Belyakov IM, Berzofsky JA (2008) Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines. Proc Natl Acad Sci USA 105(42):16260–16265. Google Scholar
  58. 58.
    Duggan JM, You D, Cleaver JO, Larson DT, Garza RJ, Guzmán Pruneda FA, Tuvim MJ, Zhang J, Dickey BF, Evans SE (2011) Synergistic interactions of TLR2/6 and TLR9 induce a high level of resistance to lung. J Immunol 186(10):5916–5926. Google Scholar
  59. 59.
    Sato A, Linehan MM, Iwasaki A (2006) Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells. Proc Natl Acad Sci USA 103:17343–17348. Google Scholar
  60. 60.
    Zhan R, Han Q, Zhang C, Tian Z, Zhang J (2015) Toll-like receptor 2 (TLR2) and TLR9 play opposing roles in host innate immunity against Salmonella enterica serovar typhimurium infection. Infect Immun 83:1641–1649. Google Scholar
  61. 61.
    Shi C, Pamer EG (2014) Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11(11):762–774. Google Scholar
  62. 62.
    Serbina NV, Pamer EG (2006) Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7:311–317. Google Scholar
  63. 63.
    Majmudar MD et al (2013) Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice. Circulation 127(20):2038–2041. Google Scholar
  64. 64.
    Leuschner F et al (2011) Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol 29(11):1005–1010. Google Scholar
  65. 65.
    Harokopakis E, Albzreh MH, Martin MH, Hajishengallis G (2006) TLR2 transmodulates monocyte adhesion and transmigration via Rac1- and PI3 K-mediated inside-out signaling in response to Porphyromonas gingivalis fimbriae. J Immunol 176(12):7645–7656. Google Scholar
  66. 66.
    Herman AC, Monlish DA, Romine MP, Bhatt ST, Zippel S, Schuettpelz LG (2016) Systemic TLR2 agonist exposure regulates hematopoietic stem cells via cell-autonomous and cell-non-autonomous mechanisms. Blood Cancer J. 6:e437. Google Scholar
  67. 67.
    Serbina NV, Kuziel W, Flavell R, Akira S, Rollins B, Pamer EG (2003) Sequential MyD88-independent and -dependent activation of innate immune responses to intracellular bacterial infection. Immunity 19(6):891–901. Google Scholar
  68. 68.
    Kurotaki D et al (2013) Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation. Blood 121(10):1839–1849. Google Scholar
  69. 69.
    Sunderkötter C et al (2004) Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol 172:4410–4417. Google Scholar
  70. 70.
    Ancuta P, Liu KY, Misra V, Wacleche VS, Gosselin A, Zhou X, Gabuzda D (2009) Transcriptional profiling reveals developmental relationship and distinct biological functions of CD16+ and CD16− monocyte subsets. BMC Genom 10:403. Google Scholar
  71. 71.
    Yona S et al (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38(1):79–91. Google Scholar
  72. 72.
    Rosenkranz ME, Schulte DJ, Agle LM, Wong MH, Zhang W et al (2005) TLR2 and MyD88 contribute to Lactobacillus casei extract-induced focal coronary arteritis in a mouse model of Kawasaki disease. Circulation 112:2966–2973Google Scholar
  73. 73.
    Lin IC et al (2012) Augmented TLR2 expression on monocytes in both human kawasaki disease and a mouse model of coronary arteritis. PLoS One 7(6):e38635. Google Scholar
  74. 74.
    Lacerte P, Brunet A, Egarnes B, Duchêne B, Brown JP, Gosselin J (2016) Overexpression of TLR2 and TLR9 on monocyte subsets of active rheumatoid arthritis patients contributes to enhance responsiveness to TLR agonists. Arthritis Res Ther 18:10. Google Scholar
  75. 75.
    Cros J, Cagnard N, Woollard K, Patey N, Zhang SY, Senechal B, Puel A, Biswas SK, Moshous D, Picard C, Jais JP, D’Cruz D, Casanova JL, Trouillet C, Geissmann F (2010) Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33(3):375–386. Google Scholar
  76. 76.
    Imhof BA, Jemelin S, Emre Y (2017) Toll-like receptors elicit different recruitment kinetics of monocytes and neutrophils in mouse acute inflammation. Eur J Immunol 47(6):1002–1008. Google Scholar
  77. 77.
    Quintar A, McArdle S, Wolf D, Marki A, Ehinger E, Vassallo M, Miller J, Mikulski Z, Ley K, Buscher K (2017) Endothelial protective monocyte patrolling in large arteries intensified by western diet and atherosclerosis. Circ Res 120(11):1789–1799. Google Scholar
  78. 78.
    Fingerle G, Pforte A, Passlick B, Blumenstein M, Ströbel M, Ziegler-Heitbrock HW (1993) The novel subset of CD14+/CD16+ blood monocytes is expanded in sepsis patients. Blood 82(10):3170–3176Google Scholar
  79. 79.
    Brilha S, Wysoczanski R, Whittington AM, Friedland JS, Porter JC (2017) Monocyte adhesion, migration, and extracellular matrix breakdown are regulated by integrin αVβ3 in Mycobacterium tuberculosis infection. J Immunol 199(3):982–999. Google Scholar
  80. 80.
    Schlitt A, Heine GH, Blankenberg S, Espinola-Klein C, Dopheide JF, Bickel C, Lackner KJ, Iz M, Meyer J, Darius H, Rupprecht HJ (2004) CD14+CD16+ monocytes in coronary artery disease and their relationship to serum TNF-α levels. Thromb Haemost 92:419–424. Google Scholar
  81. 81.
    Shahid F, Lip GYH, Shantsila E (2018) Role of monocyte in Heart failure and Atrial fibrillation. J Am Heart Assoc 7:e007849. Google Scholar
  82. 82.
    Souza PE, Rocha MO, Rocha-Vieira E, Menezes CA, Chaves AC, Gollob KJ, Dutra WO (2004) Monocytes from patients with indeterminate and cardiac forms of chagas’ disease display distinct phenotypic and functional characteristics associated with morbidity. Infect Immun 72:5283–5291. Google Scholar
  83. 83.
    Pinto BF, Medeiros NI, Teixeira-Carvalho A, Eloi-Santos SM, Fontes-Cal TCM, Rocha DA, Dutra WO, Correa-Oliveira R, Gomes JAS (2018) CD86 expression by monocytes influences an immunomodulatory profile in asymptomatic patients with chronic chagas disease. Front Immunol. 9:454. (eCollection) Google Scholar
  84. 84.
    Cruz JS, Machado FS, Ropert C, Roman-Campos D (2017) Molecular mechanisms of cardiac electromechanical remodeling during Chagas disease: role of TNF and TGF-β. Trends Cardiovasc Med 27(2):81–91. Google Scholar
  85. 85.
    Kimball A, Schaller M, Joshi A, Davis FM, denDekker A, Boniakowski A, Bermick J, Obi A, Moore B, Henke PK, Kunkel SL, Gallagher KA (2018) Ly6CHi blood monocyte/macrophage drive chronic inflammation and impair wound healing in diabetes mellitus. Arterioscler Thromb Vasc Biol 38(5):1102–1114. Google Scholar
  86. 86.
    Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ (2007) Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 117:195–205Google Scholar
  87. 87.
    Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, vanRooijen N, Lira SA, Habenicht AJ, Randolph GJ (2007) Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 117:185–194Google Scholar
  88. 88.
    Armstrong L, Medford AR, Hunter KJ, Uppington KM (2004) Millar AB (2004) Differential expression of Toll-like receptor (TLR)-2 and TLR-4 on monocytes in human sepsis. Clin Exp Immunol 136(2):312–319. Google Scholar
  89. 89.
    Gurses KM, Kocyigit D, Yalcin MU, Canpinar H, Yorgun H, Sahiner ML, Kaya EB, Oto MA, Ozer N, Guc D, Aytemir K (2016) Monocyte toll-like receptor expression in patients with atrial fibrillation. Am J Cardiol 117(9):1463–1467. Google Scholar
  90. 90.
    Konrad B, Marcovecchio P, Hedrick CC, Ley K (2017) Patrolling mechanics of non-classical monocytes in vascular inflammation. Front Cardiovasc Med 4:80. Google Scholar
  91. 91.
    Nagai Y, Garrett KP, Ohta S, Bahrun U, Kouro T, Akira S, Takatsu K, Kincade PW (2006) Hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity 24(6):801–812. Google Scholar
  92. 92.
    Yáñez A, Goodridge HS, Gozalbo D, Gil ML (2013) TLRs control hematopoiesis during infection. Eur J Immunol 43(10):2526–2533. Google Scholar
  93. 93.
    Megías J, Yáñez A, Moriano S, O’Connor JE, Gozalbo D, Gil ML (2012) Direct Toll-like receptor-mediated stimulation of hematopoietic stem and progenitor cells occurs in vivo and promotes differentiation toward macrophages. Stem cells 30(7):1486–1495. Google Scholar
  94. 94.
    Seganish WM (2016) Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015). Expert Opin Ther Pat 26(8):917–932. Google Scholar
  95. 95.
    Dudhgaonkar S et al (2017) Selective IRAK4 inhibition attenuates disease in murine lupus models and demonstrates steroid sparing activity. J Immunol 198(3):1308–1319. Google Scholar
  96. 96.
    Cushing L, Winkler A, Jelinsky SA, Lee K, Korver W, Hawtin R, Rao VR, Fleming M, Lin LL (2017) IRAK4 kinase activity controls Toll-like receptor-induced inflammation through the transcription factor IRF5 in primary human monocytes. J Biol Chem 292(45):18689–18698. Google Scholar

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Authors and Affiliations

  1. 1.Departamento de Bioquímica e Imunologia, Instituto de Ciências BiológicasUniversidade Federal de Minas GeraisBelo HorizonteBrazil

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