C1q and phagocytosis: The perfect complement to a good meal

Journal of Leukocyte Biology

Volumn 92, Issue 3, 2012, Pages 489-497

  Galvan, Manuel D ^a,b   Greenlee Wacker, Mallary C ^c   Bohlson, Suzanne S ^a,b  

^a UNIVERSITY OF NOTRE DAME   (United States)

^b INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF IOWA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPONECTIN; COMPLEMENT COMPONENT C1Q; FICOLIN 2; FICOLIN 3; MER PROTEIN; PROTEIN; PROTEIN TYROSINE KINASE; UNCLASSIFIED DRUG;

APOPTOSIS; AUTOIMMUNITY; CELL DEATH; DOWN REGULATION; MACROPHAGE; NONHUMAN; PHAGOCYTE; PHAGOCYTOSIS; PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; SYSTEMIC LUPUS ERYTHEMATOSUS;

ANIMALS; AUTOIMMUNITY; COMPLEMENT C1Q; HUMANS; MACROPHAGES; PHAGOCYTOSIS; SIGNAL TRANSDUCTION;

EID: 84865517779     PISSN: 07415400     EISSN: None     Source Type: Journal    
DOI: 10.1189/jlb.0212099     Document Type: Review

References (113)

1. Bohlson, S. S., Fraser, D. A., Tenner, A. J. (2007) Complement proteins C1q and MBL are pattern recognition molecules that signal immediate and long-term protective immune functions. Mol. Immunol. 44, 33-43.
2. Reid, K. B., Porter, R. R. (1976) Subunit composition and structure of subcomponent C1q of the first component of human complement. Biochem. J. 155, 19-23.
3. Fraser, D. A., Tenner, A. J. (2008) Directing an appropriate immune response: the role of defense collagens other soluble pattern recognition molecules. Curr. Drug Targets 9, 113-122.
4. Jiang, H., Cooper, B., Robey, F. A., Gewurz, H. (1992) DNA binds and activates complement via residues 14-26 of the human C1q A chain. J. Biol. Chem. 267, 25597-25601.
5. Jiang, H., Burdick, D., Glabe, C. G., Cotman, C. W., Tenner, A. J. (1994) β-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. J. Immunol. 152, 50505059.
6. Johns, T. G., Bernard, C. C. (1997) Binding of complement component Clq to myelin oligodendrocyte glycoprotein: a novel mechanism for regulating CNS inflammation. Mol. Immunol. 34, 33-38.
7. Tacnet-Delorme, P., Chevallier, S., Arlaud, G. J. (2001) β-Amyloid fibrils activate the C1 complex of complement under physiological conditions: evidence for a binding site for A β on the C1q globular regions. J. Immunol. 167, 6374-6381.
8. Cortes-Hernandez, J., Fossati-Jimack, L., Petry, F., Loos, M., Izui, S., Walport, M. J., Cook, H. T., Botto, M. (2004) Restoration of C1q levels by bone marrow transplantation attenuates autoimmune disease associated with C1q deficiency in mice. Eur. J. Immunol. 34, 3713-3722.
9. Petry, F., Botto, M., Holtappels, R., Walport, M. J., Loos, M. (2001) Reconstitution of the complement function in C1q-deficient (C1qa-/-) mice with wild-type bone marrow cells. J. Immunol. 167, 4033-4037.
10. Korotzer, A. R., Watt, J., Cribbs, D., Tenner, A. J., Burdick, D., Glabe, C., Cotman, C. W. (1995) Cultured rat microglia express C1q and receptor for C1q: implications for amyloid effects on microglia. Exp. Neurol. 134, 214-221.
11. Chen, G., Tan, C. S., Teh, B. K., Lu, J. (2011) Molecular mechanisms for synchronized transcription of three complement C1q subunit genes in dendritic cells and macrophages. J. Biol. Chem. 286, 34941-34950.
12. Reboul, A., Bensa, J. C., Colomb, M. G. (1986) Characteristics of complement subcomponents C1r and C1s synthesized by Hep G2 cells. Biochem. J. 233, 559-564.
13. Reboul, A., Prandini, M. H., Bensa, J. C., Colomb, M. G. (1985) Characterization of C1q, C1s and C-1 Inh synthesized by stimulated human monocytes in vitro. FEBS Lett. 190, 65-68.
14. Bensa, J. C., Reboul, A., Colomb, M. G. (1983) Biosynthesis in vitro of complement subcomponents C1q, C1s and C1 inhibitor by resting and stimulated human monocytes. Biochem. J. 216, 385-392.
15. Hortin, G. L., Trimpe, B. L. (1991) C1 inhibitor: different mechanisms of reaction with complement component C1 and C1s. Immunol. Invest. 20, 75-82.
16. Chesne, S., Villiers, C. L., Arlaud, G. J., Lacroix, M. B., Colomb, M. G. (1982) Fluid-phase interaction of C1 inhibitor (C1 Inh) and the subcomponents C1r and C1s of the first component of complement, C1. Biochem. J. 201, 61-70.
17. Bobak, D. A., Frank, M. M., Tenner, A. J. (1988) C1q acts synergisti-cally with phorbol dibutyrate to activate CR1-mediated phagocytosis by human mononuclear phagocytes. Eur. J. Immunol. 18, 2001-2007.
18. Bobak, D. A., Gaither, T. A., Frank, M. M., Tenner, A. J. (1987) Modulation of FcR function by complement: subcomponent C1q enhances the phagocytosis of IgG-opsonized targets by human monocytes and culture-derived macrophages. J. Immunol. 138, 1150-1156.
19. Botto, M., Walport, M. J. (2002) C1q, autoimmunity and apoptosis. Immunobiology 205, 395-406.
20. Mevorach, D., Mascarenhas, J. O., Gershov, D., Elkon, K. B. (1998) Complement-dependent clearance of apoptotic cells by human macrophages. J. Exp. Med. 188, 2313-2320.
21. Fraser, D. A., Pisalyaput, K., Tenner, A. J. (2010) C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J. Neurochem. 112, 733-743.
22. Vandivier, R. W., Ogden, C. A., Fadok, V. A., Hoffmann, P. R., Brown, K. K., Botto, M., Walport, M. J., Fisher, J. H., Henson, P. M., Greene, K. E. (2002) Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J. Immunol. 169, 3978-3986.
23. Ogden, C. A., deCathelineau, A., Hoffmann, P. R., Bratton, D., Ghe-brehiwet, B., Fadok, V. A., Henson, P. M. (2001) C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med. 194, 781-795.
24. Paidassi, H., Tacnet-Delorme, P., Garlatti, V., Darnault, C., Ghebrehi-wet, B., Gaboriaud, C., Arlaud, G. J., Frachet, P. (2008) C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J. Immunol. 180, 2329-2338.
25. Fraser, D. A., Arora, M., Bohlson, S. S., Lozano, E., Tenner, A. J. (2007) Generation of inhibitory NFKB complexes and phosphorylated cAMP response element-binding protein correlates with the anti-inflammatory activity of complement protein C1q in human monocytes. J. Biol. Chem. 282, 7360-7367.
26. Tenner, A. J., Robinson, S. L., Ezekowitz, R. A. (1995) Mannose binding protein (MBP) enhances mononuclear phagocyte function via a receptor that contains the 126,000 M(r) component of the C1q receptor. Immunity 3, 485-493.
27. Tenner, A. J., Robinson, S. L., Borchelt, J., Wright, J. R. (1989) Human pulmonary surfactant protein (SP-A), a protein structurally homologous to C1q, can enhance FcR-and CR1-mediated phagocytosis. J. Biol. Chem. 264, 13923-13928.
28. Webster, S. D., Galvan, M. D., Ferran, E., Garzon-Rodriguez, W., Glabe C. G., Tenner, A. J. (2001) Antibody-mediated phagocytosis of the amy loid β-peptide in microglia is differentially modulated by C1q. J. Immunol. 166, 7496-7503.
29. Arora, M., Munoz, E., Tenner, A. J. (2001) Identification of a site on mannan-binding lectin critical for enhancement of phagocytosis. J. Biol Chem. 276, 43087-43094.
30. Tenner, A. J., Cooper, N. R. (1981) Identification of types of cells in human peripheral blood that bind C1q. J. Immunol. 126, 1174-1179.
31. Bajtay, Z., Jozsi, M., Banki, Z., Thiel, S., Thielens, N., Erdei, A. (2000) Mannan-binding lectin and C1q bind to distinct structures and exert differential effects on macrophages. Eur. J. Immunol. 30, 1706-1713.
32. Tenner, A. J., Cooper, N. R. (1982) Stimulation of a human polymorphonuclear leukocyte oxidative response by the C1q subunit of the first complement component. J. Immunol. 128, 2547-2552.
33. Vegh, Z., Kew, R R, Gruber, B. L., Ghebrehiwet, B. (2006) Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR Mol. Immunol. 43, 1402-1407.
34. Leigh, L. E., Ghebrehiwet, B., Perera, T. P., Bird, I. N., Strong, P., Kishore, U., Reid, K. B., Eggleton, P. (1998) C1q-mediated chemotaxis by human neutrophils: involvement of gClqR and G-protein signalling mechanisms. Biochem. J. 330, 247-254.
35. Oroszlan, M., Daha, M. R., Cervenak, L., Prohaszka, Z., Fust, G., Roos, A. (2007) MBL and C1q compete for interaction with human endothelial cells. Mol. Immunol. 44, 1150-1158.
36. Lillis, A. P., Greenlee, M. C., Mikhailenko, I., Pizzo, S. V., Tenner, A. J., Strickland, D. K., Bohlson, S. S. (2008) Murine low-density lipoprotein receptor-related protein 1 (LRP) is required for phagocytosis of targets bearing LRP ligands but is not required for C1q-triggered enhancement of phagocytosis. J. Immunol. 181, 364-373.
37. Stuart, G. R., Lynch, N. J., Day, A. J Schwaeble, W. J., Sim, R. B. (1997) The C1q and collectin binding site within C1q receptor (cell surface calreticulin). Immunopharmacology 38, 73-80.
38. Chao, M. P., Jaiswal, S., Weissman-Tsukamoto, R., Alizadeh, A. A., Gentles, A. J., Volkmer, J., Weiskopf, K., Willingham, S. B., Raveh, T., Park, C. Y., Majeti, R., Weissman, I. L. (2010) Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci. Transl. Med. 2, 63ra94.
39. Lillis, A. P., Mikhailenko, I., Strickland, D. K. (2005) Beyond endocyto-sis: LRP function in cell migration, proliferation and vascular permeability. J. Thromb. Haemost. 3, 1884-1893.
40. Duus, K., Hansen, E. W., Tacnet, P., Frachet, P., Arlaud, G. J., Thiel-ens, N. M., Houen, G. (2010) Direct interaction between CD91 and C1q. FEBS J. 277, 3526-3537.
41. Greenlee, M. C., Sullivan, S. A., Bohlson, S. S. (2008) CD93 and related family members: their role in innate immunity. Curr. Drug Targets 9, 130-138.
42. Norsworthy, P. J., Fossati-Jimack, L., Cortes-Hernandez, J., Taylor, P. R., Bygrave, A. E., Thompson, R. D., Nourshargh, S., Walport, M. J., Botto, M. (2004) Murine CD93 (C1qRp) contributes to the removal of apo-ptotic cells in vivo but is not required for C1q-mediated enhancement of phagocytosis. J. Immunol. 172, 3406-3414.
43. Klickstein, L. B., Barbashov, S. F., Liu, T., Jack, R. M., Nicholson-Weller, A. (1997) Complement receptor type 1 (CR1, CD35) is a receptor for C1q. Immunity 7, 345-355.
44. Edelson, B. T., Stricker, T. P., Li, Z., Dickeson, S. K., Shepherd, V. L., Santoro, S. A., Zutter, M. M. (2006) Novel collectin/C1q receptor mediates mast cell activation and innate immunity. Blood 107, 143-150.
45. Eggleton, P., Lieu, T. S., Zappi, E. G., Sastry, K., Coburn, J., Zaner, K. S., Sontheimer, R. D., Capra, J. D., Ghebrehiwet, B., Tauber, A. I. (1994) Calreticulin is released from activated neutrophils and binds to C1q and mannan-binding protein. Clin. Immunol. Immunopathol. 72, 405-409.
46. Kozmar, A., Greenlee-Wacker, M. C., Bohlson, S. S. (2010) Macrophage response to apoptotic cells varies with the apoptotic trigger and is not altered by a deficiency in LRP expression. J. Innate Immun. 2, 248-259.
47. Serezani, C. H., Aronoff, D. M., Sitrin, R. G., Peters-Golden, M. (2009) FcyRI ligation leads to a complex with BLT1 in lipid rafts that enhances rat lung macrophage antimicrobial functions. Blood 114, 33163324.
48. Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y., Shimizu, T. (1997) A G-protein-coupled receptor for leukotriene B4 that mediates che-motaxis. Nature 387, 620-624.
49. Mancuso, P., Standiford, T. J., Marshall, T., Peters-Golden, M. (1998) 5-Lipoxygenase reaction products modulate alveolar macrophage phagocytosis of Klebsiella pneumoniae. Infect. Immun. 66, 5140-5146.
50. Park, D., Tosello-Trampont, A. C., Elliott, M. R., Lu, M., Haney, L. B., Ma, Z., Klibanov, A. L., Mandell, J. W., Ravichandran, K S. (2007) BAI1 is an engulfment receptor for apoptotic cells upstream of the EL-MO/Dock180/Rac module. Nature 450, 430-434.
51. Park, S. Y., Jung, M. Y., Kim, H. J., Lee, S. J., Kim, S. Y., Lee, B. H., Kwon, T. H., Park, R. W., Kim, I. S. (2008) Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ. 15, 192-201.
52. Miyanishi, M., Tada, K, Koike, M., Uchiyama, Y., Kitamura, T., Nagata, S. (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435-439.
53. Dekruyff, R. H., Bu, X., Ballesteros, A., Santiago, C., Chim, Y. L., Lee, H. H., Karisola, P., Pichavant, M., Kaplan, G. G., Umetsu, D. T., Freeman, G. J., Casasnovas, J. M. (2010) T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J. Immunol. 184, 1918-1930.
54. Hanayama, R., Tanaka, M., Miwa, K, Shinohara, A., Iwamatsu, A., Na-gata, S. (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417, 182-187.
55. Ishimoto, Y., Ohashi, K, Mizuno, K, Nakano, T. (2000) Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, Gas6. J. Biochem. 127, 411-417.
56. Gardai, S. J., McPhillips, K A., Frasch, S. C., Janssen, W. J., Starefeldt, A., Murphy-Ullrich, J. E., Bratton, D. L., Oldenborg, P. A., Michalak, M., Henson, P. M. (2005) Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321-334.
57. Erwig, L. P., Henson, P. M. (2007) Immunological consequences of apoptotic cell phagocytosis. Am. J. Pathol. 171, 2-8.
58. Munoz, L. E., Lauber, K, Schiller, M., Manfredi, A. A., Herrmann, M. (2010) The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat. Rev. Rheumatol. 6, 280-289.
59. Munoz, L. E., Peter, C., Herrmann, M., Wesselborg, S., Lauber, K (2010) Scent of dying cells: the role of attraction signals in the clearance of apoptotic cells and its immunological consequences. Autoim-mun. Rev. 9, 425-430.
60. Antolin, J., Amerigo, M. J., Cantabrana, A., Roces, A., Jimenez, P. (1995) Systemic lupus erythematosus: clinical manifestations and immunological parameters in 194 patients. Subgroup classification of SLE. Clin. Rheumatol. 14, 678-685.
61. D'Cruz, D. P., Khamashta, M. A., Hughes, G. R. (2007) Systemic lupus erythematosus. Lancet 369, 587-596.
62. Pickering, M. C., Botto, M., Taylor, P. R., Lachmann, P. J., Walport, M. J. (2000) Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv. Immunol. 76, 227-324.
63. Martens, H. A., Zuurman, M. W., de Lange, A. H., Nolte, I. M., van der Steege, G., Navis, G.J., Kallenberg, C. G., Seelen, M. A., Bijl, M. (2009) Analysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity. Ann. Rheum. Dis. 68, 715-720.
64. Botto, M., Dell'Agnola, C., Bygrave, A. E., Thompson, E. M., Cook, H. T., Petry, F., Loos, M., Pandolfi, P. P., Walport, M.J. (1998) Ho mozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat. Genet. 19, 56-59.
65. Mitchell, D. A., Pickering, M. C., Warren, J., Fossati-Jimack, L., Cortes-Hernandez, J., Cook, H. T., Botto, M., Walport, M.J. (2002) C1q deficiency and autoimmunity: the effects of genetic background on disease expression. J. Immunol. 168, 2538-2543.
66. Taylor, P. R., Carugati, A., Fadok, V. A., Cook, H. T., Andrews, M., Carroll, M. C., Savill, J. S., Henson, P. M., Botto, M., Walport, M. J. (2000) A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359-366.
67. Nauta, A. J., Trouw, L. A., Daha, M. R., Tijsma, O., Nieuwland, R., Schwaeble, W. J., Gingras, A. R., Mantovani, A., Hack, E. C., Roos, A. (2002) Direct binding of C1q to apoptotic cells and cell blebs induces complement activation. Eur. J. Immunol. 32, 1726-1736.
68. Quartier, P., Potter, P. K, Ehrenstein, M. R., Walport, M. J., Botto, M. (2005) Predominant role of IgM-dependent activation of the classical pathway in the clearance of dying cells by murine bone marrow-derived macrophages in vitro. Eur. J. Immunol. 35, 252-260.
69. Donnelly, S., Roake, W., Brown, S., Young, P., Naik, H., Wordsworth, P., Isenberg, D. A., Reid, K B., Eggleton, P. (2006) Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus. Arthritis Rheum. 54, 1543-1556.
70. Fraser, D. A., Laust, A. K, Nelson, E. L., Tenner, A. J. (2009) C1q differentially modulates phagocytosis and cytokine responses during ingestion of apoptotic cells by human monocytes, macrophages, and dendritic cells. J. Immunol. 183, 6175-6185.
71. Takizawa, F., Tsuji, S., Nagasawa, S. (1996) Enhancement of macrophage phagocytosis upon iC3b deposition on apoptotic cells. FEBS Lett. 397, 269-272.
72. Kim, S.J., Gershov, D., Ma, X., Brot, N., Elkon, K B. (2002) I-PLA(2) activation during apoptosis promotes the exposure of membrane lyso-phosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation. J. Exp. Med. 196, 655-665.
73. Chen, Y., Park, Y. B., Patel, E., Silverman, G. J. (2009) IgM antibodies to apoptosis-associated determinants recruit C1q and enhance dendritic cell phagocytosis of apoptotic cells. J. Immunol. 182, 6031-6043.
74. Korb, L. C., Ahearn, J. M. (1997) C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J. Immunol. 158, 4525-4528.
75. Navratil, J. S., Korb, L. C., Ahearn, J. M. (1999) Systemic lupus erythematosus and complement deficiency: clues to a novel role for the classical complement pathway in the maintenance of immune tolerance. Immunopharmacology 42, 47-52.
76. Sjoberg, A. P., Trouw, L. A., Blom, A. M. (2009) Complement activation and inhibition: a delicate balance. Trends Immunol. 30, 83-90.
77. Gardai, S. J., Bratton, D. L., Ogden, C. A., Henson, P. M. (2006) Recognition ligands on apoptotic cells: a perspective. J. Leukoc. Biol. 79, 896-903.
78. Nauta, A. J., Castellano, G., Xu, W., Woltman, A. M., Borrias, M. C., Daha, M. R., van, K C., Roos, A. (2004) Opsonization with C1q and mannose-binding lectin targets apoptotic cells to dendritic cells. J. Immunol. 173, 3044-3050.
79. Stuart, L. M., Takahashi, K, Shi, L., Savill, J., Ezekowitz, R. A. (2005) Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype. J. Immunol. 174, 3220-3226.
80. Schagat, T. L., Wofford, J. A., Wright, J. R. (2001) Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils. J. Immunol. 166, 2727-2733.
81. Schagat, T. L., Wofford, J. A., Greene, K E., Wright, J. R. (2003) Surfactant protein A differentially regulates peripheral and inflammatory neutrophil chemotaxis. Am. J. Physiol. Lung Cell. Mol. Physiol. 284, L140-L147.
82. Reidy, M. F., Wright, J. R. (2003) Surfactant protein A enhances apo-ptotic cell uptake and TGF-β! release by inflammatory alveolar macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L854-L861.
83. Kuraya, M., Ming, Z., Liu, X., Matsushita, M., Fujita, T. (2005) Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology 209, 689-697.
84. Jensen, M. L., Honore, C., Hummelshoj, T., Hansen, B. E., Madsen, H. O., Garred, P. (2007) Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol. Immunol. 44, 856-865.
85. Honore, C., Hummelshoj, T., Hansen, B. E., Madsen, H. O., Eggleton, P., Garred, P. (2007) The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum. 56, 1598-1607.
86. Scherer, P. E., Williams, S., Fogliano, M., Baldini, G., Lodish, H. F. (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746-26749.
87. Takemura, Y., Ouchi, N., Shibata, R., Aprahamian, T., Kirber, M. T., Summer, R. S., Kihara, S., Walsh, K. (2007) Adiponectin modulates inflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies. J. Clin. Invest. 117, 375-386.
88. Zwart, B., Ciurana, C., Rensink, I., Manoe, R., Hack, C. E., Aarden, L. A. (2004) Complement activation by apoptotic cells occurs predomi nantly via IgM and is limited to late apoptotic (secondary necrotic) cells. Autoimmunity 37, 95-102.
89. Ehrenstein, M. R., Cook, H. T., Neuberger, M. S. (2000) Deficiency in serum immunoglobulin (Ig)M predisposes to development of IgG autoantibodies. J. Exp. Med. 191, 1253-1258.
90. Boes, M., Schmidt, T., Linkemann, K., Beaudette, B. C., Marshak-Roth-stein, A., Chen, J. (2000) Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proc. Natl. Acad. Sci. USA 97, 1184-1189.
91. Gullstrand, B., Martensson, U., Sturfelt, G., Bengtsson, A. A., Truedsson, L. (2009) Complement classical pathway components are all important in clearance of apoptotic and secondary necrotic cells. Clin. Exp. Immunol. 156, 303-311.
92. Botto, M., Kirschfink, M., Macor, P., Pickering, M. C., Wurzner, R., Te-desco, F. (2009) Complement in human diseases: lessons from complement deficiencies. Mol. Immunol. 46, 2774-2783.
93. Graham, D. K., Salzberg, D. B., Kurtzberg, J., Sather, S., Matsushima, G. K., Keating, A. K, Liang, X., Lovell, M. A., Williams, S. A., Dawson, T. L., Schell, M.J., Anwar, A. A., Snodgrass, H. R., Earp, H. S. (2006) Ectopic expression of the proto-oncogene Mer in pediatric T-cell acute lymphoblastic leukemia. Clin. Cancer Res. 12, 2662-2669.
94. Keating, A. K, Salzberg, D. B., Sather, S., Liang, X., Nickoloff, S., Anwar, A., Deryckere, D., Hill, K, Joung, D., Sawczyn, K K, Park, J., Cur-ran-Everett, D., McGavran, L., Meltesen, L., Gore, L., Johnson, G. L., Graham, D. K. (2006) Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase. Oncogene 25, 6092-6100.
95. Graham, D. K, Dawson, T. L., Mullaney, D. L., Snodgrass, H. R., Earp, H. S. (1994) Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. Cell Growth Differ. 5, 647-657.
96. Graham, D. K, Bowman, G. W., Dawson, T. L., Stanford, W. L., Earp, H. S., Snodgrass, H. R. (1995) Cloning and developmental expression analysis of the murine c-mer tyrosine kinase. Oncogene 10, 2349-2359.
97. Scott, R. S., McMahon, E. J., Pop, S. M., Reap, E. A., Caricchio, R., Cohen, P. L., Earp, H. S., Matsushima, G. K (2001) Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207-211.
98. Cohen, P. L., Caricchio, R., Abraham, V., Camenisch, T. D., Jennette, J. C., Roubey, R. A., Earp, H. S., Matsushima, G., Reap, E. A. (2002) Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J. Exp. Med. 196, 135-140.
99. Duncan, J. L., LaVail, M. M., Yasumura, D., Matthes, M. T., Yang, H., Trautmann, N., Chappelow, A. V., Feng, W., Earp, H. S., Matsushima, G. K, Vollrath, D. (2003) An RCS-like retinal dystrophy phenotype in mer knockout mice. Invest. Ophthalmol. Vis. Sci. 44, 826-838.
100. Prasad, D., Rothlin, C. V., Burrola, P., Burstyn-Cohen, T., Lu, Q., Garcia de, F. P., Lemke, G. (2006) TAM receptor function in the retinal pigment epithelium. Mol. Cell. Neurosci. 33, 96-108.
101. D'Cruz, P. M., Yasumura, D., Weir, J., Matthes, M. T., Abderrahim, H., LaVail, M. M., Vollrath, D. (2000) Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum. Mol. Genet. 9, 645-651.
102. Nandrot, E., Dufour, E. M., Provost, A. C., Pequignot, M. O., Bonnel, S., Gogat, K, Marchant, D., Rouillac, C., Sepulchre de Conde, B., Biho-reau, M. T., Shaver, C., Dufier, J. L., Marsac, C., Lathrop, M., Men-asche, M., Abitbol, M. M. (2000) Homozygous deletion in the coding sequence of the c-mer gene in RCS rats unravels general mechanisms of physiological cell adhesion and apoptosis. Neurobiol. Dis. 7, 586-599.
103. Feng, W., Yasumura, D., Matthes, M. T., LaVail, M. M., Vollrath, D. (2002) Mertk triggers uptake of photoreceptor outer segments during phagocytosis by cultured retinal pigment epithelial cells. J. Biol. Chem. 277, 17016-17022.
104. Hall, M. O., Obin, M. S., Heeb, M.J., Burgess, B. L., Abrams, T. A. (2005) Both protein S and Gas6 stimulate outer segment phagocytosis by cultured rat retinal pigment epithelial cells. Exp. Eye Res. 81, 581591.
105. Gal, A., Li, Y., Thompson, D. A., Weir, J., Orth, U., Jacobson, S. G., Apfelstedt-Sylla, E., Vollrath, D. (2000) Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat. Genet. 26, 270-271.
106. Ksantini, M., Lafont, E., Bocquet, B., Meunier, I., Hamel, C. P. (2011) Homozygous mutation in MERTK causes severe autosomal recessive retinitis pigmentosa. Eur. J. Ophthalmol., 22, 647-653.
107. Manfioletti, G., Brancolini, C., Avanzi, G., Schneider, C. (1993) The protein encoded by a growth arrest-specific gene (Gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol. Cell. Biol. 13, 4976-4985.
108. Caberoy, N. B., Zhou, Y., Li, W. (2010) Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis. EMBO J. 29, 3898-3910.
109. Caberoy, N. B., Alvarado, G., Bigcas, J. L., Li, W. (2012) Galectin-3 is a new MerTK-specific eat-me signal. J. Cell. Physiol. 227, 401-407.
110. Galvan, M. D., Foreman, D. B., Zeng, E., Tan, J. C., Bohlson, S. S. (2012) Complement component c1q regulates macrophage expression of mer tyrosine kinase to promote clearance of apoptotic cells. J. Immunol. 188, 3716-3723.
111. Roszer, T., Menendez-Gutierrez, M. P., Lefterova, M. I., Alameda, D., Nunez, V., Lazar, M. A., Fischer, T., Ricote, M. (2011) Autoimmune kidney disease and impaired engulfment of apoptotic cells in mice with macrophage peroxisome proliferator-activated receptor y or retinoid X receptor a deficiency. J. Immunol. 186, 621-631.
112. A-Gonzalez, N., Bensinger, S. J., Hong, C., Beceiro, S., Bradley, M. N., Zelcer, N., Deniz, J., Ramirez, C., Diaz, M., Gallardo, G., de Galarreta, C. R., Salazar, J., Lopez, F., Edwards, P., Parks, J., Andujar, M., Tonto-noz, P., Castrillo, A. (2009) Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31, 245-258.
113. Mukundan, L., Odegaard, J. I., Morel, C. R., Heredia, J. E., Mwangi, J. W., Ricardo-Gonzalez, R. R., Goh, Y. P., Eagle, A. R., Dunn, S. E., Awakuni, J. U., Nguyen, K D., Steinman, L., Michie, S. A., Chawla, A. (2009) PPAR-5 senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat. Med. 15, 1266-1272.