Discovery of carboxyethylpyrroles (CEPs): Critical insights into AMD, autism, cancer, and wound healing from basic research on the chemistry of oxidized phospholipids

Chemical Research in Toxicology

Volumn 24, Issue 11, 2011, Pages 1803-1816

  Salomon, Robert G ^a   Hong, Li ^a   Hollyfield, Joe G ^b  

^a CASE WESTERN RESERVE UNIVERSITY   (United States)

^b CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CARBOXYPROPYLPYRROLE; CATALASE; COPPER ZINC SUPEROXIDE DISMUTASE; GLUTATHIONE PEROXIDASE; OXIDIZED PHOSPHOLIPID; PHOSPHOLIPID; PYRROLE DERIVATIVE; REACTIVE OXYGEN METABOLITE; RHODOPSIN; SUPEROXIDE DISMUTASE; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 4; UNCLASSIFIED DRUG; VASCULOTROPIN;

ANGIOGENESIS; ANTIANGIOGENIC ACTIVITY; AUTISM; BLOOD RETINA BARRIER; BRUCH MEMBRANE; CONFORMATIONAL TRANSITION; DISEASE EXACERBATION; DRUSEN; ENDOCYTOSIS; ENDOTHELIUM CELL; HUMAN; IMMUNOHISTOCHEMISTRY; LIPID BILAYER; LIPID OXIDATION; NEOPLASM; NONHUMAN; OXIDATIVE STRESS; PHAGOLYSOSOME; PHOTORECEPTOR OUTER SEGMENT; RETINA MACULA AGE RELATED DEGENERATION; REVIEW; SUBRETINAL NEOVASCULARIZATION; WOUND HEALING;

ANIMALS; ANTIBODIES; ANTIGENS, CD36; AUTISTIC DISORDER; CORNEA; CORNEAL NEOVASCULARIZATION; ENDOTHELIAL CELLS; HUMANS; MACULAR DEGENERATION; MICE; MICE, KNOCKOUT; NEOPLASMS; OXIDATION-REDUCTION; PHOSPHOLIPIDS; PROTEIN PROCESSING, POST-TRANSLATIONAL; PYRROLES; RETINAL ROD PHOTORECEPTOR CELLS; TOLL-LIKE RECEPTOR 2; WOUND HEALING;

EID: 81755168911     PISSN: 0893228X     EISSN: 15205010     Source Type: Journal    
DOI: 10.1021/tx200206v     Document Type: Review

References (75)

1. Sayre, L. M., Sha, W., Xu, G., Kaur, K., Nadkarni, D., Subbanagounder, G., and Salomon, R. G. (1996) Immunochemical evidence supporting 2-pentylpyrrole formation on proteins exposed to 4-hydroxy-2-nonenal Chem. Res. Toxicol. 9, 1194-1201 (Pubitemid 26347974)
2. Kaur, K., Salomon, R. G., ONeil, J., and Hoff, H. F. (1997) (Carboxyalkyl)pyrroles in human plasma and oxidized low-density lipoproteins Chem. Res. Toxicol. 10, 1387-1396 (Pubitemid 28018928)
3. Skinner, E. R., Watt, C., Besson, J. A., and Best, P. V. (1993) Differences in the fatty acid composition of the grey and white matter of different regions of the brains of patients with Alzheimers disease and control subjects Brain 116 (Pt 3) 717-725 (Pubitemid 23203646)
4. Alvarez, R. A., Aguirre, G. D., Acland, G. M., and Anderson, R. E. (1994) Docosapentaenoic acid is converted to docosahexaenoic acid in the retinas of normal and prcd-affected miniature poodle dogs Invest. Ophthalmol. Vis. Sci. 35, 402-408 (Pubitemid 24078093)
5. Wang, N. and Anderson, R. E. (1992) Enrichment of polyunsaturated fatty acids from rat retinal pigment epithelium to rod outer segments Curr. Eye Res. 11, 783-791
6. Gu, X., Sun, M., Gugiu, B., Hazen, S., Crabb, J. W., and Salomon, R. G. (2003) Oxidatively truncated docosahexaenoate phospholipids: total synthesis, generation, and peptide adduction chemistry J. Org. Chem. 68, 3749-3761 (Pubitemid 36576624)
7. Hoff, H. F., ONeil, J., Wu, Z., Hoppe, G., and Salomon, R. L. (2003) Phospholipid hydroxyalkenals: biological and chemical properties of specific oxidized lipids present in atherosclerotic lesions Arterioscler., Thromb., Vasc. Biol. 23, 275-282 (Pubitemid 36231940)
8. Gu, X., Meer, S. G., Miyagi, M., Rayborn, M. E., Hollyfield, J. G., Crabb, J. W., and Salomon, R. G. (2003) Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age-related macular degeneration J. Biol. Chem. 278, 42027-42035 (Pubitemid 37310467)
9. Lu, L., Gu, X., Hong, L., Laird, J., Jaffe, K., Choi, J., Crabb, J., and Salomon, R. G. (2009) Synthesis and structural characterization of carboxyethylpyrrole-modified proteins: mediators of age-related macular degeneration Bioorg. Med. Chem. 17, 7548-7561
10. Salomon, R. G. and Gu, X. (2011) Critical insights into cardiovascular disease from basic research on the oxidation of phospholipids: the γ-hydroxyalkenal phospholipid hypothesis Chem. Res. Toxicol. 10.1021/tx200207z
11. Podrez, E. A., Poliakov, E., Shen, Z., Zhang, R., Deng, Y., Sun, M., Finton, P. J., Shan, L., Febbraio, M., Hajjar, D. P., Silverstein, R. L., Hoff, H. F., Salomon, R. G., and Hazen, S. L. (2002) A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions J. Biol. Chem. 277, 38517-38523 (Pubitemid 35154710)
12. Podrez, E. A., Poliakov, E., Shen, Z., Zhang, R., Deng, Y., Sun, M., Finton, P. J., Shan, L., Gugiu, B., Fox, P. L., Hoff, H. F., Salomon, R. G., and Hazen, S. L. (2002) Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36 J. Biol. Chem. 277, 38503-38516 (Pubitemid 35154709)
13. Hayes, K. C., Lindsey, S., Stephan, Z. F., and Brecker, D. (1989) Retinal pigment epithelium possesses both LDL and scavenger receptor activity Invest. Ophthalmol. Vis. Sci. 30, 225-232 (Pubitemid 19055599)
14. Gordiyenko, N., Campos, M., Lee, J. W., Fariss, R. N., Sztein, J., and Rodriguez, I. R. (2004) RPE cells internalize low-density lipoprotein (LDL) and oxidized LDL (oxLDL) in large quantities in vitro and in vivo Invest. Ophthalmol. Vis. Sci. 45, 2822-2829 (Pubitemid 38998882)
15. Choi, J., Laird, J. M., and Salomon, R. G. (2011) An efficient synthesis of γ-hydroxy-α,β-unsaturated aldehydic esters of 2-lysophosphatidylcholine Bioorg. Med. Chem. 19, 580-7
16. Deng, Y. and Salomon, R. G. (1998) Total synthesis of γ-hydroxy-α,β-unsaturated aldehydic esters of cholesterol and 2-lysophosphatidylcholine J. Org. Chem. 63, 7789-7794
17. Sun, M., Finnemann, S. C., Febbraio, M., Shan, L., Annangudi, S. P., Podrez, E. A., Hoppe, G., Darrow, R., Organisciak, D. T., Salomon, R. G., Silverstein, R. L., and Hazen, S. L. (2006) Light-induced oxidation of photoreceptor outer segment phospholipids generates ligands for CD36-mediated phagocytosis by retinal pigment epithelium: a potential mechanism for modulating outer segment phagocytosis under oxidant stress conditions J. Biol. Chem. 281, 4222-4230 (Pubitemid 43847851)
18. Evans, J. R. (2001) Risk factors for age-related macular degeneration Prog. Retinal Eye Res. 20, 227-253 (Pubitemid 32149928)
19. Klein, R., Klein, B. E., and Linton, K. L. (1992) Prevalence of age-related maculopathy. The Beaver Dam Eye Study Ophthalmology 99, 933-943
20. AREADS-Research-Group (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch. Ophthalmol. 119, 1417-1436.
21. Beatty, S., Koh, H., Phil, M., Henson, D., and Boulton, M. (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration Surv. Ophthalmol. 45, 115-34
22. Gu, J., Paeur, G. J., Yue, X., Narendra, U., Sturgill, G. M., Bena, J., Gu, X., Peachey, N. S., Salomon, R. G., Hagstrom, S. A., Crabb, J. W., Clinical, G., and Proteomic Study, G. (2009) Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers Mol. Cell Proteomics 8, 1338-1349
23. Crabb, J. W., Miyagi, M., Gu, X., Shadrach, K., West, K. A., Sakaguchi, H., Kamei, M., Hasan, A., Yan, L., Rayborn, M. E., Salomon, R. G., and Hollyfield, J. G. (2002) Drusen proteome analysis: an approach to the etiology of age-related macular degeneration Proc. Natl. Acad. Sci. U.S.A. 99, 14682-14687 (Pubitemid 35334544)
24. Back, S. A., Luo, N. L., Mallinson, R. A., OMalley, J. P., Wallen, L. D., Frei, B., Morrow, J. D., Petito, C. K., Roberts, C. T., Jr., Murdoch, G. H., and Montine, T. J. (2005) Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes Ann. Neurol. 58, 108-120 (Pubitemid 40962466)
25. Meagher, E. A. and FitzGerald, G. A. (2000) Indices of lipid peroxidation in vivo: strengths and limitations Free Radical Biol. Med. 28, 1745-1750 (Pubitemid 30628661)
26. Chauhan, A. and Chauhan, V. (2006) Oxidative stress in autism Pathophysiology 13, 171-181
27. Keller, F. and Persico, A. M. (2003) The neurobiological context of autism Mol. Neurobiol. 28, 1-22 (Pubitemid 38156433)
28. Zoroglu, S. S., Armutcu, F., Ozen, S., Gurel, A., Sivasli, E., Yetkin, O., and Meram, I. (2004) Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism Eur. Arch. Psychiatry Clin. Neurosci. 254, 143-147 (Pubitemid 39304462)
29. Golse, B., Debray-Ritzen, P., Durosay, P., Puget, K., and Michelson, A. M. (1978) Alterations in two enzymes: superoxide dismutase and glutathion peroxidase in developmental infantile psychosis (infantile autism) (authors transl.) Rev. Neurol. (Paris) 134, 699-705 (Pubitemid 9083214)
30. Yorbik, O., Sayal, A., Akay, C., Akbiyik, D. I., and Sohmen, T. (2002) Investigation of antioxidant enzymes in children with autistic disorder Prostaglandins, Leukotrienes Essent. Fatty Acids 67, 341-343 (Pubitemid 35397373)
31. James, S. J., Cutler, P., Melnyk, S., Jernigan, S., Janak, L., Gaylor, D. W., and Neubrander, J. A. (2004) Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism Am. J. Clin. Nutr. 80, 1611-1617 (Pubitemid 41103861)
32. James, S. J., Melnyk, S., Jernigan, S., Cleves, M. A., Halsted, C. H., Wong, D. H., Cutler, P., Bock, K., Boris, M., Bradstreet, J. J., Baker, S. M., and Gaylor, D. W. (2006) Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism Am. J. Med. Genet., Part B 141B, 947-956 (Pubitemid 44905454)
33. Evans, T. A., Siedlak, S. L., Lu, L., Fu, X., Wang, Z., McGinnis, W. R., Fakhoury, E., Castellani, R. J., Hazen, S. L., Walsh, W. J., Lewis, A. T., Salomon, R. G., Smith, M. A., Perry, G., and Zhu, X. (2008) The autistic phenotype exhibits a remarkably localized modification of brain protein by products of free radical-induced lipid oxidation Am. J. Biotechnol. Biochem. 4, 61-72 (Pubitemid 351573640)
34. Castelli, F., Frith, C., Happe, F., and Frith, U. (2002) Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes Brain 125, 1839-1849
35. Just, M. A., Cherkassky, V. L., Keller, T. A., Kana, R. K., and Minshew, N. J. (2007) Functional and anatomical cortical underconnectivity in autism: evidence from an FMRI study of an executive function task and corpus callosum morphometry Cereb. Cortex 17, 951-961 (Pubitemid 46434636)
36. Just, M. A., Cherkassky, V. L., Keller, T. A., and Minshew, N. J. (2004) Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity Brain 127, 1811-1821 (Pubitemid 39061557)
37. Koshino, H., Carpenter, P. A., Minshew, N. J., Cherkassky, V. L., Keller, T. A., and Just, M. A. (2005) Functional connectivity in an fMRI working memory task in high-functioning autism Neuroimage 24, 810-821 (Pubitemid 40094563)
38. Mottron, L., Burack, J. A., Iarocci, G., Belleville, S., and Enns, J. T. (2003) Locally oriented perception with intact global processing among adolescents with high-functioning autism: evidence from multiple paradigms J. Child Psychol. Psychiatry 44, 904-913 (Pubitemid 37059226)
39. Smith, M. A., Sayre, L. M., Anderson, V. E., Harris, P. L., Beal, M. F., Kowall, N., and Perry, G. (1998) Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4-dinitrophenylhydrazine J. Histochem. Cytochem. 46, 731-735 (Pubitemid 28272207)
40. West, X. Z., Malinin, N. L., Merkulova, A. A., Tischenko, M., Kerr, B. A., Borden, E. C., Podrez, E. A., Salomon, R. G., and Byzova, T. V. (2010) Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands Nature 467, 972-976
41. Hageman, G. S., Luthert, P. J., Victor Chong, N. H., Johnson, L. V., Anderson, D. H., and Mullins, R. F. (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruchs membrane interface in aging and age-related macular degeneration Prog. Retinal Eye Res. 20, 705-732 (Pubitemid 32918285)
42. Johnson, L. V., Ozaki, S., Staples, M. K., Erickson, P. A., and Anderson, D. H. (2000) A potential role for immune complex pathogenesis in drusen formation Exp. Eye Res. 70, 441-449 (Pubitemid 30662042)
43. Penfold, P. L., Madigan, M. C., Gillies, M. C., and Provis, J. M. (2001) Immunological and aetiological aspects of macular degeneration Prog. Retinal Eye Res. 20, 385-414 (Pubitemid 32245687)
44. Mullins, R. F., Russell, S. R., Anderson, D. H., and Hageman, G. S. (2000) Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease FASEB J. 14, 835-846 (Pubitemid 30241660)
45. Edwards, A. O., Ritter, R., III, Abel, K. J., Manning, A., Panhuysen, C., and Farrer, L. A. (2005) Complement factor H polymorphism and age-related macular degeneration Science 308, 421-424 (Pubitemid 40530082)
46. Gold, B., Merriam, J. E., Zernant, J., Hancox, L. S., Taiber, A. J., Gehrs, K., Cramer, K., Neel, J., Bergeron, J., Barile, G. R., Smith, R. T., Hageman, G. S., Dean, M., and Allikmets, R. (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration Nat. Genet. 38, 458-462
47. Hageman, G. S., Anderson, D. H., Johnson, L. V., Hancox, L. S., Taiber, A. J., Hardisty, L. I., Hageman, J. L., Stockman, H. A., Borchardt, J. D., Gehrs, K. M., Smith, R. J., Silvestri, G., Russell, S. R., Klaver, C. C., Barbazetto, I., Chang, S., Yannuzzi, L. A., Barile, G. R., Merriam, J. C., Smith, R. T., Olsh, A. K., Bergeron, J., Zernant, J., Merriam, J. E., Gold, B., Dean, M., and Allikmets, R. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration Proc. Natl. Acad. Sci. U.S.A. 102, 7227-7232 (Pubitemid 40696361)
48. Haines, J. L., Hauser, M. A., Schmidt, S., Scott, W. K., Olson, L. M., Gallins, P., Spencer, K. L., Kwan, S. Y., Noureddine, M., Gilbert, J. R., Schnetz-Boutaud, N., Agarwal, A., Postel, E. A., and Pericak-Vance, M. A. (2005) Complement factor H variant increases the risk of age-related macular degeneration Science 308, 419-421 (Pubitemid 40530081)
49. Klein, R. J., Zeiss, C., Chew, E. Y., Tsai, J. Y., Sackler, R. S., Haynes, C., Henning, A. K., SanGiovanni, J. P., Mane, S. M., Mayne, S. T., Bracken, M. B., Ferris, F. L., Ott, J., Barnstable, C., and Hoh, J. (2005) Complement factor H polymorphism in age-related macular degeneration Science 308, 385-389 (Pubitemid 40530070)
50. Yates, J. R., Sepp, T., Matharu, B. K., Khan, J. C., Thurlby, D. A., Shahid, H., Clayton, D. G., Hayward, C., Morgan, J., Wright, A. F., Armbrecht, A. M., Dhillon, B., Deary, I. J., Redmond, E., Bird, A. C., and Moore, A. T. (2007) Complement C3 variant and the risk of age-related macular degeneration N. Engl. J. Med. 357, 553-561 (Pubitemid 47236280)
51. Hollyfield, J. G., Bonilha, V. L., Rayborn, M. E., Yang, X., Shadrach, K. G., Lu, L., Ufret, R. L., Salomon, R. G., and Perez, V. L. (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration Nat. Med. 14, 194-198 (Pubitemid 351214555)
52. Hollyfield, J. G., Perez, V. L., and Salomon, R. G. (2010) A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration Mol. Neurobiol. 41, 290-298
53. Ambati, J., Anand, A., Fernandez, S., Sakurai, E., Lynn, B. C., Kuziel, W. A., Rollins, B. J., and Ambati, B. K. (2003) An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice Nat. Med. 9, 1390-1397 (Pubitemid 37466188)
54. Cousins, S. W., Espinosa-Heidmann, D. G., Alexandridou, A., Sall, J., Dubovy, S., and Csaky, K. (2002) The role of aging, high fat diet and blue light exposure in an experimental mouse model for basal laminar deposit formation Exp. Eye Res. 75, 543-553 (Pubitemid 35435609)
55. Gottsch, J. D., Bynoe, L. A., Harlan, J. B., Rencs, E. V., and Green, W. R. (1993) Light-induced deposits in Bruchs membrane of protoporphyric mice Arch. Ophthalmol. 111, 126-129 (Pubitemid 23022901)
56. Malek, G., Johnson, L. V., Mace, B. E., Saloupis, P., Schmechel, D. E., Rickman, D. W., Toth, C. A., Sullivan, P. M., and Bowes Rickman, C. (2005) Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration Proc. Natl. Acad. Sci. U.S.A. 102, 11900-11905 (Pubitemid 41170822)
57. Bressler, S. B., Maguire, M. G., Bressler, N. M., and Fine, S. L. (1990) Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. The Macular Photocoagulation Study Group Arch. Ophthalmol. 108, 1442-1447 (Pubitemid 20344701)
58. Sarks, S. H., Van Driel, D., Maxwell, L., and Killingsworth, M. (1980) Softening of drusen and subretinal neovascularization Trans. Ophthalmol. Soc. U. K. 100, 414-422 (Pubitemid 11088109)
59. Ebrahem, Q., Renganathan, K., Sears, J., Vasanji, A., Gu, X., Lu, L., Salomon, R. G., Crabb, J. W., and Anand-Apte, B. (2006) Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration Proc. Natl. Acad. Sci. U.S.A. 103, 13480-13484 (Pubitemid 44380133)
60. Avraamides, C. J., Garmy-Susini, B., and Varner, J. A. (2008) Integrins in angiogenesis and lymphangiogenesis Nat. Rev. Cancer 8, 604-617
61. Somanath, P. R. and Byzova, T. V. (2009) 14-3-3beta-Rac1-p21 activated kinase signaling regulates Akt1-mediated cytoskeletal organization, lamellipodia formation and fibronectin matrix assembly J. Cell Physiol. 218, 394-404
62. Osada, Y., Sunatani, T., Kim, I. S., Nakanishi, Y., and Shiratsuchi, A. (2009) Signalling pathway involving GULP, MAPK and Rac1 for SR-BI-induced phagocytosis of apoptotic cells J. Biochem. 145, 387-394
63. Wilkinson, B., Koenigsknecht-Talboo, J., Grommes, C., Lee, C. Y., and 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 (Pubitemid 44115425)
64. Arbibe, L., Mira, J. P., Teusch, N., Kline, L., Guha, M., Mackman, N., Godowski, P. J., Ulevitch, R. J., and Knaus, U. G. (2000) Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway Nat. Immunol. 1, 533-540
65. Eitel, J., Krull, M., Hocke, A. C., NGuessan, P. D., Zahlten, J., Schmeck, B., Slevogt, H., Hippenstiel, S., Suttorp, N., and Opitz, B. (2008) Beta-PIX and Rac1 GTPase mediate trafficking and negative regulation of NOD2 J. Immunol. 181, 2664-2671
66. Equils, O., Madak, Z., Liu, C., Michelsen, K. S., Bulut, Y., and Lu, D. (2004) Rac1 and Toll-IL-1 receptor domain-containing adapter protein mediate Toll-like receptor 4 induction of HIV-long terminal repeat J. Immunol. 172, 7642-7646 (Pubitemid 38747629)
67. Grote, K., Schuett, H., Salguero, G., Grothusen, C., Jagielska, J., Drexler, H., Muhlradt, P. F., and Schieffer, B. (2010) Toll-like receptor 2/6 stimulation promotes angiogenesis via GM-CSF as a potential strategy for immune defense and tissue regeneration Blood 115, 2543-2552
68. Mullick, A. E., Tobias, P. S., and Curtiss, L. K. (2005) Modulation of atherosclerosis in mice by Toll-like receptor 2 J. Clin. Invest. 115, 3149-3156 (Pubitemid 41567579)
69. Edfeldt, K., Swedenborg, J., Hansson, G. K., and Yan, Z. Q. (2002) Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation Circulation 105, 1158-1161 (Pubitemid 34225814)
70. Schjetne, K. W., Thompson, K. M., Nilsen, N., Flo, T. H., Fleckenstein, B., Iversen, J. G., Espevik, T., and Bogen, B. (2003) Cutting edge: link between innate and adaptive immunity: Toll-like receptor 2 internalizes antigen for presentation to CD4+ T cells and could be an efficient vaccine target J. Immunol. 171, 32-36 (Pubitemid 36745270)
71. Tang, S. C., Arumugam, T. V., Xu, X., Cheng, A., Mughal, M. R., Jo, D. G., Lathia, J. D., Siler, D. A., Chigurupati, S., Ouyang, X., Magnus, T., Camandola, S., and Mattson, M. P. (2007) Pivotal role for neuronal Toll-like receptors in ischemic brain injur y and functional deficits Proc. Natl. Acad. Sci. U.S.A. 104, 13798-13803 (Pubitemid 350003400)
72. Jack, C. S., Arbour, N., Manusow, J., Montgrain, V., Blain, M., McCrea, E., Shapiro, A., and Antel, J. P. (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes J. Immunol. 175, 4320-4330 (Pubitemid 41361966)
73. Lehnardt, S., Henneke, P., Lien, E., Kasper, D. L., Volpe, J. J., Bechmann, I., Nitsch, R., Weber, J. R., Golenbock, D. T., and Vartanian, T. (2006) A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia J. Immunol. 177, 583-592 (Pubitemid 43939172)
74. Babcock, A. A., Wirenfeldt, M., Holm, T., Nielsen, H. H., Dissing-Olesen, L., Toft-Hansen, H., Millward, J. M., Landmann, R., Rivest, S., Finsen, B., and Owens, T. (2006) Toll-like receptor 2 signaling in response to brain injury: an innate bridge to neuroinflammation J. Neurosci. 26, 12826-12837 (Pubitemid 44904578)
75. Yao, H., Felfly, H., Wang, J., Zhou, D., and Haddad, G. G. (2009) DIDS protects against neuronal injury by blocking Toll-like receptor 2 activated-mechanisms J. Neurochem. 108, 835-846