Advertisement

Innate Apoptotic Immunity: A Potent Immunosuppressive Response Repertoire Elicited by Specific Apoptotic Cell Recognition

  • David S. Ucker

Abstract

Phagocytosis, of course, is essential for the clearance of dying cells, and for the degradation of dying cell constituents, including the processing of potential cellular [auto]antigens. Independent of engulfment, the specific recognition of dying cells by phagocytes and other cells elicits a profound repertoire of outcomes. In particular, apoptotic cells are potently suppressive of inflammation and other immunological responses. Immunosuppressive apoptotic effects are elicited in macrophages and dendritic cells, and they are triggered in non-professional phagocytes as well. Among these responses, the immediate-early suppression of specific gene transcription is most evident. The array of genes suppressed upon apoptotic recognition includes pro-inflammatory cytokines and angiogenic factors. The ability of apoptotic cells to elicit these responses depends upon their cell surface expression of specific determinants for recognition. A variety of molecules has been implicated in this process, although the identification of definitive recognition determinants remains incomplete. The suppressive effects exerted by apoptotic cells do not arise as a simple antagonism of stimulatory signals. Selective responsiveness to apoptotic cell recognition occurs independent of known immune receptors and signalling pathways. Remarkably, specific apoptotic recognition, in contrast to all other cases of immune discrimination, exhibits no self-bias. These observations suggest that innate apoptotic immunity represents an unconventional and ubiquitous immune responsiveness—in essence, a second dimension of immunity distinct from the classical self/other axis. The subversion by pathogens (including viruses) of this suppressive responsiveness underscores the physiological significance of innate apoptotic immunity.

Apoptosis Cell death Inflammation Innate immunity Phagocytosis Signal transduction Transcriptional repression Pathogenesis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Akira S, Takeda K, Kaisho T (2001) Toll-like receptors:critical proteins linking innate and acquired immunity. Nat Immunol 2 (8):675–680PubMedGoogle Scholar
  2. Albert ML, Kim JI, Birge RB (2000) αvβ5 integrin recruits the CrkII-Dock180-Rac1 complex for phagocytosis of apoptotic cells. Nat Cell Biol 2:899–905PubMedGoogle Scholar
  3. Albert ML, Sauter B, Bhardwaj N (1998) Dendritic cells acquire antigen from apoptotic cells and induce class 1- restricted CTLs. Nature 392:86–89PubMedGoogle Scholar
  4. Appelt U, Sheriff A, Gaipl US et al (2005) Viable, apoptotic and necrotic monocytes expose phosphatidylserine:cooperative binding of the ligand Annexin V to dying but not viable cells and implications for PS-dependent clearance. Cell Death Differ 12 (2):194–196PubMedGoogle Scholar
  5. Baetz A, Frey M, Heeg K et al (2004) Suppressor of cytokine signalling (SOCS) proteins indirectly regulate toll-like receptor signalling in innate immune cells. J Biol Chem 279 (52):54708–54715Google Scholar
  6. Bailey ST, Ghosh S (2005) ‘PPAR’ting ways with inflammation. Nat Immunol 6 (10):966–967PubMedGoogle Scholar
  7. Banerjee A, Gugasyan R, McMahon M et al (2006) Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells. Proc Natl Acad Sci U S A 103 (9):3274–3279PubMedGoogle Scholar
  8. Blander JM, Medzhitov R (2004) Regulation of phagosome maturation by signals from toll-like receptors. Science 304:1014–1018PubMedGoogle Scholar
  9. Botto M, Dell’Agnola C, Bygrave AE, et al (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 19:56–59PubMedGoogle Scholar
  10. Brouckaert G, Kalai M, Krysko DV et al (2004) Phagocytosis of necrotic cells by macrophages is phosphatidylserine-dependent and does not induce inflammatory cytokine production. Mol Biol Cell 15:1089–1100PubMedGoogle Scholar
  11. Brugnera E, Haney L, Grimsley C et al (2002) Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat Cell Biol 4:574–582PubMedGoogle Scholar
  12. Burgert HG, Kvist S (1985) An adenovirus type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigens. Cell 41 (3):987–997PubMedGoogle Scholar
  13. Callahan MK, Halleck MS, Krahling S et al (2003) Phosphatidylserine expression and phagocytosis of apoptotic thymocytes during differentiation of monocytic cells. J Leukocyte Biol 74 (5):846–856PubMedGoogle Scholar
  14. Carmody RJ, Ruan Q, Palmer S et al (2007) Negative regulation of toll-like receptor signalling by NF-κB p50 ubiquitination blockade. Science 317 (5838):675–678PubMedGoogle Scholar
  15. Casciola-Rosen LA, Anhalt G, Rosen A (1994) Autoantigens targeted in systemic lupus erythematosus are clustered in two population of surface structures on apoptotic keratinocytes. J Exp Med 179:1317–1339PubMedGoogle Scholar
  16. Chang B, Chen Y, Zhao Y et al (2007) JMJD6 is a histone arginine demethylase. Science 318 (5849):444–447PubMedGoogle Scholar
  17. Chen C-J, Kono H, Golenbock D et al (2007) Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med 13 (7):851–856PubMedGoogle Scholar
  18. Chen Q, Stone PR, McCowan LM et al (2006) Phagocytosis of necrotic but not apoptotic trophoblasts induces endothelial cell activation. Hypertension 47 (1):116–121PubMedGoogle Scholar
  19. Chiou S-K, Tseng C-C, Rao L et al (1994) Functional complementation of the adenovirus E1B 19-kilodalton protein with Bcl-2 in the inhibition of apoptosis in infected cells. J Virol 68 (10):6553–6566PubMedGoogle Scholar
  20. Clarke PG, Clarke S (1996) Nineteenth century research on naturally occurring cell death and related phenomena. Anat Embryol 193:81–99PubMedGoogle Scholar
  21. Clem RJ, Miller LK (1993) Apoptosis reduces both the in vitro replication and the in vivo infectivity of a baculovirus. J Virol 67:3730–3738PubMedGoogle Scholar
  22. Cocca BA, Cline AM, Radic MZ (2002) Blebs and apoptotic bodies are B cell autoantigens. J Immunol 169:159–166PubMedGoogle Scholar
  23. Cocco RE, Ucker DS (2001) Distinct modes of macrophage recognition for apoptotic and necrotic cells are not specified exclusively by phosphatidylserine exposure. Mol Biol Cell 12 (4):919–930PubMedGoogle Scholar
  24. Cohen PL, Caricchio R, Abraham V et al (2002) Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med 196:135–140PubMedGoogle Scholar
  25. Collart MA, Baeuerle P, Vassalli P (1990) Regulation of tumour necrosis factor alpha transcription in macrophages:involvement of four κB-like motifs and of constitutive and inducible forms of NF-κB. Mol Cell Biol 10:1498–1506PubMedGoogle Scholar
  26. Collins T (1993) Endothelial nuclear factor-κB and the initiation of the atherosclerotic lesion. Lab Invest 68 (5):499–508PubMedGoogle Scholar
  27. Creagh EM, O’Neill LA (2006) TLRs, NLRs and RLRs:a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol 27 (8):352–357PubMedGoogle Scholar
  28. Cvetanovic M, Mitchell JE, Patel V et al (2006) Specific recognition of apoptotic cells reveals a ubiquitous and unconventional innate immunity. J Biol Chem 281:20055–20067PubMedGoogle Scholar
  29. Cvetanovic M, Ucker DS (2004) Innate immune discrimination of apoptotic cells:repression of proinflammatory macrophage transcription is coupled directly to specific recognition. J Immunol 172:880–889PubMedGoogle Scholar
  30. De Santa F, Totaro MG, Prosperini E et al (2007) The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130 (6):1083–1094PubMedGoogle Scholar
  31. Debbas M, White E (1993) Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev 7:546–554PubMedGoogle Scholar
  32. Decker T, Stockinger S, Karaghiosoff M et al (2002) IFNs and STATs in innate immunity to microorganisms. J Clin Invest 109 (10):1271–1277PubMedGoogle Scholar
  33. Degenhardt K, Mathew R, Beaudoin B et al (2006) Autophagy promotes tumour cell survival and restricts necrosis, inflammation, and tumourigenesis. Cancer Cell 10 (1):51–64PubMedGoogle Scholar
  34. Devitt A, Moffatt OD, Raykundalia C et al (1998) Human CD14 mediates recognition of phagocytosis of apoptotic cells. Nature 392:505–509PubMedGoogle Scholar
  35. Devitt A, Parker KG, Ogden CA et al (2004) Persistence of apoptotic cells without autoimmune disease or inflammation in CD14-/- mice. J Cell Biol 167:1161–1170PubMedGoogle Scholar
  36. Duvall E, Wyllie AH, Morris RG (1985) Macrophage recognition of cells undergoing programmed cell death (apoptosis). Immunology 56:351–358PubMedGoogle Scholar
  37. Fadok VA, Bratton DL, Konowal A et al (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J Clin Invest 101:890–898PubMedGoogle Scholar
  38. Fadok VA, Bratton DL, Rose DM et al (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405:85–90PubMedGoogle Scholar
  39. Fadok VA, Voelker DR, Campbell PA et al (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216PubMedGoogle Scholar
  40. Fitzgerald KA, Palsson-McDermott EM, Bowie AG et al (2001) Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413:78–83PubMedGoogle Scholar
  41. Foy E, Li K, Wang C et al (2003) Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300 (5622):1145–1148PubMedGoogle Scholar
  42. Franz S, Frey B, Sheriff A et al (2006) Lectins detect changes of the glycosylation status of plasma membrane constituents during late apoptosis. Cytometry A 69 (4):230–239PubMedGoogle Scholar
  43. Freire-de-Lima CG, Nascimento DO, Soares MB et al (2000) Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature 403:199–203PubMedGoogle Scholar
  44. Freire-de-Lima CG, Xiao YQ, Gardai SJ et al (2006) Apoptotic cells, through transforming growth factor-β, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J Biol Chem 281 (50):38376–38384PubMedGoogle Scholar
  45. Gardai SJ, McPhillips KA, Frasch SC et al (2005) Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321–334PubMedGoogle Scholar
  46. Gerritsen ME, Williams AJ, Neish AS et al (1997) CREB-binding protein/p300 are transcriptional coactivators of p65. Proc Natl Acad Sci U S A 94:2927–2932PubMedGoogle Scholar
  47. Goldfeld AE, McCaffrey PG, Strominger JL et al (1993) Identification of a novel cyclosporinsensitive element in the human tumour necrosis factor alpha gene promoter. J Exp Med 178:1365–1379PubMedGoogle Scholar
  48. Grigera F, Ucker DS unpublished dataGoogle Scholar
  49. Guha M, Mackman N (2002) The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signalling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem 277 (35):32124–32132PubMedGoogle Scholar
  50. Hanayama R, Tanaka M, Miyasaka K et al (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304:1147–1150PubMedGoogle Scholar
  51. Harzenetter MD, Novotny AR, Gais P et al (2007) Negative regulation of TLR responses by the neuropeptide CGRP is mediated by the transcriptional repressor ICER. J Immunol 179 (1):607–615PubMedGoogle Scholar
  52. Henson PM, Johnston RB Jr (1987) Tissue injury in inflammation:oxidants, proteinases, and cationic proteins. J Clin Invest 79:669–674PubMedGoogle Scholar
  53. Hirt UA, Leist M (2003) Rapid, noninflammatory and PS-dependent phagocytic clearance of necrotic cells. Cell Death Differ 10 (10):1156–1164PubMedGoogle Scholar
  54. Hoberg JE, Yeung F, Mayo MW (2004) SMRT derepression by the IκB kinase α:a prerequisite to NF-κB transcription and survival. Mol Cell 16:245–255PubMedGoogle Scholar
  55. Hoffmann PR, deCathelineau AM, Ogden CA et al (2001) Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J Cell Biol 155:649–660PubMedGoogle Scholar
  56. Horng T, Barton GM, Medzhitov R (2001) TIRAP:an adapter molecule in the Toll signalling pathway. Nat Immunol 2:835–841PubMedGoogle Scholar
  57. Hoshino K, Kaisho T, Iwabe T et al (2002) Differential involvement of IFN-βin Toll-like receptorstimulated dendritic cell activation. Int Immunol 14 (10):1225–1231PubMedGoogle Scholar
  58. Hoshino K, Takeuchi O, Kawai T et al (1999) Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide:evidence for TLR4 as the Lps gene product. J Immunol 162:3749–3752PubMedGoogle Scholar
  59. Hughes J, Liu Y, Damme JV et al (1997) Human glomerular mesangial cell phagocytosis of apoptotic neutrophils. J Immunol 158:4389–4397PubMedGoogle Scholar
  60. Johann AM, von Knethen A, Lindemann D et al (2006) Recognition of apoptotic cells by macrophages activates the peroxisome proliferator-activated receptor-γand attenuates the oxidative burst. Cell Death Differ 13 (9):1533–1540PubMedGoogle Scholar
  61. Johann AM, Weigert A, Eberhardt W et al (2008) Apoptotic cell-derived sphingosine-1-phosphate promotes HuR-dependent cyclooxygenase-2 mRNA stabilization and protein expression. J Immunol 180 (2):1239–1248PubMedGoogle Scholar
  62. Kawai T, Adachi O, Ogawa T et al (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115–122PubMedGoogle Scholar
  63. Kerr JFR, Wyllie AH, Currie AR (1972) Apoptosis:a basic biological phenomenon with wideranging implications in tissue kinetics. Br J Cancer 26:239–256PubMedGoogle Scholar
  64. Kim S, Elkon KB, Ma X (2004) Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells. Immunity 21:643–653PubMedGoogle Scholar
  65. Kinjyo I, Hanada T, Inagaki-Ohara K et al (2002) SOCS1/JAB is a negative regulator of LPSinduced macrophage activation. Immunity 17 (5):583–591PubMedGoogle Scholar
  66. Kleinclauss F, Perruche S, Masson E et al (2006) Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion. Cell Death Differ 13:41–52PubMedGoogle Scholar
  67. Kobayashi K, Hernandez LD, Galan JE et al (2002) IRAK-M is a negative regulator of Toll-like receptor signalling. Cell 110 (2):191–202PubMedGoogle Scholar
  68. Kurosaka K, Watanabe N, Kobayashi Y (1998) Production of proinflammatory cytokines by phorbol myristate acetate-treated THP-1 cells and monocyte-derived macrophages after phagocytosis of apoptotic CTLL-2 cells. J Immunol 161:6245–6249PubMedGoogle Scholar
  69. Lamioni A, Parisi F, Isacchi G et al (2005) The immunological effects of extracorporeal photopheresis unraveled:induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo. Transplantation 79:846–850PubMedGoogle Scholar
  70. Lauber K, Bohn E, Kröber SM et al (2003) Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113:717–730PubMedGoogle Scholar
  71. Lehner MD, Morath S, Michelsen KS et al (2001) Induction of cross-tolerance by lipopolysaccharide and highly purified lipoteichoic acid via different Toll-like receptors independent of paracrine mediators. J Immunol 166 (8):5161–5167PubMedGoogle Scholar
  72. Li M, Carpio DF, Zheng Y et al (2001) An essential role of the NF-κB/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. J Immunol 166:7128–7135PubMedGoogle Scholar
  73. Liu K, Iyoda T, Saternus M et al (2002) Immune tolerance after delivery of dying cells to dendritic cells in situ. J Exp Med 196:1091–1097PubMedGoogle Scholar
  74. Maeda A, Schwarz A, Kernebeck K et al (2005) Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells. J Immunol 174:5968–5976PubMedGoogle Scholar
  75. Majái G, Sarang Z, Csomós K et al (2007) PPARγ-dependent regulation of human macrophages in phagocytosis of apoptotic cells. Eur J Immunol 37 (5):1343–1354PubMedGoogle Scholar
  76. Marguet D, Luciani MF, Moynault A et al (1999) Engulfment of apoptotic cells involves the redistribution of membrane phosphatidylserine on phagocyte and prey. Nat Cell Biol 1:454–456PubMedGoogle Scholar
  77. Matzinger P (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12:991–1045PubMedGoogle Scholar
  78. Matzinger P (2002) The danger model:a renewed sense of self. Science 296 (5566):301–305PubMedGoogle Scholar
  79. McDonald PP, Fadok VA, Bratton D et al (1999) Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-γin macrophages that have ingested apoptotic cells. J Immunol 163 (11):6164–6172PubMedGoogle Scholar
  80. McEvoy L, Williamson P, Schlegel RA (1986) Membrane phospholipid asymmetry as a determinant of erythrocyte recognition by macrophages. Proc Natl Acad Sci U S A 83:3311–3315PubMedGoogle Scholar
  81. Meagher LC, Savill JS, Baker A et al (1992) Phagocytosis of apoptotic neutrophils does not induce macrophage release of thromboxane B2. J Leukocyte Biol 52:269–272PubMedGoogle Scholar
  82. Medvedev AE, Sabroe I, Hasday JD et al (2006) Tolerance to microbial TLR ligands:molecular mechanisms and relevance to disease. J Endotoxin Res 12 (3):133–150PubMedGoogle Scholar
  83. Medzhitov R, Preston-Hurlburt P, Kopp E et al (1998) MyD88 is an adaptor protein in the hToll/IL- 1 receptor family signalling pathways. Mol Cell 2:253–258PubMedGoogle Scholar
  84. Metchnikoff E (1891) Leçons sur la pathologie comparée de l’inflammation. Dover Publications, New York, p 224Google Scholar
  85. Mevorach D, Mascarenhas JO, Gershov D et al (1998) Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med 188:2313–2320PubMedGoogle Scholar
  86. Mitchell JE, Cvetanovic M, Tibrewal N et al (2006) The presumptive phosphatidylserine receptor is dispensable for innate anti- inflammatory recognition and clearance of apoptotic cells. J Biol Chem 281:5718–5725PubMedGoogle Scholar
  87. Mitchell JE, Ucker DS unpublished dataGoogle Scholar
  88. Monks J, Rosner D, Geske FJ et al (2005) Epithelial cells as phagocytes:apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release. Cell Death Differ 12:107–114PubMedGoogle Scholar
  89. Nakagawa R, Naka T, Tsutsui H et al (2002) SOCS-1 participates in negative regulation of LPS responses. Immunity 17 (5):677–687PubMedGoogle Scholar
  90. Nandrot EF, Kim Y, Brodie SE et al (2004) Loss of synchronized retinal phagocytosis and agerelated blindness in mice lacking αvβ5 integrin. J Exp Med 200:1539–1545PubMedGoogle Scholar
  91. Nauta AJ, Trouw LA, Daha MR et al (2002) Direct binding of C1q to apoptotic cells and cell blebs induces complement activation. Eur J Immunol 32:1726–1736PubMedGoogle Scholar
  92. Nouri-Shirazi M, Banchereau J, Bell D et al (2000) Dendritic cells capture killed tumour cells and present their antigens to elicit tumour-specific immune responses. J Immunol 165:3797–3803PubMedGoogle Scholar
  93. Obeid M, Tesniere A, Ghiringhelli F et al (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13 (1):54–61PubMedGoogle Scholar
  94. Parnaik R, Raff MC, Scholes J (2000) Differences between the clearance of apoptotic cells by professional and non- professional phagocytes. Curr Biol 10:857–860PubMedGoogle Scholar
  95. Patel VA, Longacre-Antoni A, Cvetanovic M et al (2007) The affirmative response of the innate immune system to apoptotic cells. Autoimmunity 40 (4):274–280PubMedGoogle Scholar
  96. Patel VA, Longacre A, Hsiao K et al (2006) Apoptotic cells, at all stages of the death process, trigger characteristic signalling events that are divergent from and dominant over those triggered by necrotic cells:implications for the delayed clearance model of autoimmunity. J Biol Chem 281 (8):4663–4670PubMedGoogle Scholar
  97. Petrovski G, Zahuczky G, Majái G et al (2007) Phagocytosis of cells dying through autophagy evokes a pro-inflammatory response in macrophages. Autophagy 3 (5):509–511PubMedGoogle Scholar
  98. Platanias LC (2005) Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev:Immunol 5 (5):375–386PubMedGoogle Scholar
  99. Poltorak A, He X, Smirnova I et al (1998) Defective LPS signalling in C3H/HeJ and C57BL/ 10ScCr mice:mutations in Tlr4 gene. Science 282 (5396):2085–2088PubMedGoogle Scholar
  100. Pradhan D, Krahling S, Williamson P et al (1997) Multiple systems for recognition of apoptotic lymphocytes by macrophages. Mol Biol Cell 8:767–778PubMedGoogle Scholar
  101. Raabe T, Bukrinsky M, Currie RA (1998) Relative contribution of transcription and translation to the induction of tumour necrosis factor-αby lipopolysaccharide. J Biol Chem 273:974–980PubMedGoogle Scholar
  102. Radke JR, Cook JL, Ucker DS unpublished dataGoogle Scholar
  103. Ray CA, Black RA, Kronheim SR et al (1992) Viral inhibition of inflammation:cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme. Cell 69 (4):597–604PubMedGoogle Scholar
  104. Reddy SM, Hsiao KH, Abernethy VE et al (2002) Phagocytosis of apoptotic cells by macrophages induces novel signalling events leading to cytokine-independent survival and inhibition of proliferation:activation of Akt and inhibition of extracellular signal-regulated kinases 1 and 2. J Immunol 169 (2):702–713PubMedGoogle Scholar
  105. Ronchetti A, Rovere P, Iezzi G et al (1999) Immunogenicity of apoptotic cells in vivo:role of antigen load, antigen- presenting cells, and cytokines. J Immunol 163:130–136PubMedGoogle Scholar
  106. Rothlin CV, Ghosh S, Zuniga EI et al (2007) TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131 (6):1124–1136PubMedGoogle Scholar
  107. Saunders JW Jr (1966) Death in embryonic systems. Science 154:604–612PubMedGoogle Scholar
  108. Sauter B, Albert ML, Francisco L et al (2000) Consequences of cell death:exposure to necrotic tumour cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med 191:423–434PubMedGoogle Scholar
  109. Savill J, Dransfield I, Gregory C et al (2002) A blast from the past:clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2:965–975PubMedGoogle Scholar
  110. Savill JS, Wyllie AH, Henson JE et al (1989) Macrophage phagocytosis of aging neutrophils in inflammation:programmed cell death in the neutrophil leads to its recognition by macrophages. J Clin Invest 83:865–875PubMedGoogle Scholar
  111. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195PubMedGoogle Scholar
  112. Schlegel RA, Stevens M, Lumley-Sapanski K et al (1993) Altered lipid packing identifies apoptotic thymocytes. Immunol Lett 36:283–288PubMedGoogle Scholar
  113. Schroit AJ, Madsen JW, Tanaka Y (1985) In vitro recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes. J Biol Chem 260:5131–5138PubMedGoogle Scholar
  114. Sen P, Wallet MA, Yi Z, Huang Y et al (2007) Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-κB activation in dendritic cells. Blood 109 (2):653–660PubMedGoogle Scholar
  115. Shakhov AN, Collart MA, Vassalli P et al (1990) κB-type enhancers are involved in lipopolysaccharide- mediated transcriptional activation of the tumour necrosis factor αgene in primary macrophages. J Exp Med 171:35–47PubMedGoogle Scholar
  116. Shi Y, Evans JE, Rock KL (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425 (6957):516–521PubMedGoogle Scholar
  117. Shweiki D, Itin A, Soffer D et al (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359 (6398):843–845PubMedGoogle Scholar
  118. Škoberne M, Beignon A-S, Larsson M et al (2005) Apoptotic cells at the crossroads of tolerance and immunity. Curr Top Microbiol Immunol 289:259–292PubMedGoogle Scholar
  119. Sly LM, Rauh MJ, Kalesnikoff J et al (2004) LPS-induced upregulation of SHIP is essential for endotoxin tolerance. Immunity 21 (2):227–239PubMedGoogle Scholar
  120. Stern M, Savill J, Haslett C (1996) Human monocyte-derived macrophage phagocytosis of senescent eosinophils undergoing apoptosis:mediation by αVβ3/CD36/thrombospondin recognition mechanism and lack of phlogistic response. Am J Pathol 149:911–921PubMedGoogle Scholar
  121. Stranges PB, Watson J, Cooper CJ et al (2007) Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity. Immunity 26 (5):629–641PubMedGoogle Scholar
  122. Stuart GR, Lynch NJ, Day AJ et al (1997) The C1q and collectin binding site within C1q receptor (cell surface calreticulin). Immunopharmacology 38 (1–2):73–80Google Scholar
  123. Stuart LM, Lucas M, Simpson C et al (2002) Inhibitory effects of apoptotic cell ingestion upon endotoxin-driven myeloid dendritic cell maturation. J Immunol 168 (4):1627–1635PubMedGoogle Scholar
  124. Suchin KR, Cassin M, Washko R et al (1999) Extracorporeal photochemotherapy does not suppress T- or B-cell responses to novel or recall antigens. J Am Acad Dermatol 41:980–986PubMedGoogle Scholar
  125. Suzuki N, Suzuki S, Duncan GS et al (2002) Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416:750–756PubMedGoogle Scholar
  126. Tassiulas I, Park-Min K-H, Hu Y et al (2007) Apoptotic cells inhibit LPS-induced cytokine and chemokine production and IFN responses in macrophages. Hum Immunol 68 (3):156–164PubMedGoogle Scholar
  127. Toshchakov V, Jones BW, Perera P-Y et al (2002) TLR4, but not TLR2, mediates IFN-β-induced STAT1α/β-dependent gene expression in macrophages. Nat Immunol 3 (4):392–398PubMedGoogle Scholar
  128. van ‘t Veer C, Van Den Pangaart PS, van Zoelen MAD et al (2007) Induction of IRAK-M is associated with lipopolysaccharide tolerance in a human endotoxemia model. J Immunol 179 (10):7110–7120PubMedGoogle Scholar
  129. Vanden Berghe W, De Bosscher K, Boone E et al (1999) The nuclear factor-κB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. J Biol Chem 274:32091–32098Google Scholar
  130. Voll RE, Herrmann M, Roth EA et al (1997) Immunosuppressive effects of apoptotic cells. Nature 390:350–351PubMedGoogle Scholar
  131. Wanderley JLM, Moreira MEC, Benjamin A et al (2006) Mimicry of apoptotic cells by exposing phosphatidylserine participates in the establishment of amastigotes of Leishmania (L) amazonensis in mammalian hosts. J Immunol 176 (3):1834–1839PubMedGoogle Scholar
  132. Weigert A, Johann AM, von Knethen A et al (2006) Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate. Blood 108 (5):1635–1642PubMedGoogle Scholar
  133. Werts C, Girardin SE, Philpott DJ (2006) TIR, CARD and PYRIN:three domains for an antimicrobial triad. Cell Death Differ 13 (5):798–815PubMedGoogle Scholar
  134. Witko-Sarsat V, Rieu P, Descamps-Latscha B et al (2000) Neutrophils:molecules, functions and pathophysiological aspects. Lab Invest 80 (5):617–653PubMedGoogle Scholar
  135. Wood W, Turmaine M, Weber R et al (2000) Mesenchymal cells engulf and clear apoptotic footplate cells in macrophageless PU.1 null mouse embryos. Development 127:5245–5252PubMedGoogle Scholar
  136. Wyllie AH, Kerr JFR, Currie AR (1980) Cell death:the significance of apoptosis. Int Rev Cytol 68:251–305PubMedGoogle Scholar
  137. Xiao YQ, Malcolm K, Worthen GS et al (2002) Cross-talk between ERK and p38 MAPK mediates selective suppression of pro- inflammatory cytokines by transforming growth factor-β. J Biol Chem 277 (17):14884–14893PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • David S. Ucker
    • 1
  1. 1.Department of Microbiology and ImmunologyUniversity of Illinois College of MedicineChicago

Personalised recommendations