Red cell DAMPs and inflammation

Inflammation Research

Volumn 65, Issue 9, 2016, Pages 665-678

  Mendonça, Rafaela ^a   Silveira, Angélica A A ^a   Conran, Nicola ^a  

^a UNIVERSITY OF CAMPINAS   (Brazil)

Author keywords

DAMPs; Hemolysis; Inflammasome; Red blood cells; Sickle cell disease; Toll like receptor

Indexed keywords

ADENOSINE; ADENOSINE TRIPHOSPHATE; HEME; HEMOGLOBIN; HEMOPEXIN; HEMOPROTEIN; INFLAMMASOME; TOLL LIKE RECEPTOR; ALARMIN;

BETA THALASSEMIA; CELL STIMULATION; ERYTHROCYTE; ERYTHROCYTE DISORDER; HEMOLYTIC ANEMIA; HEREDITARY HEMOLYTIC ANEMIA; HUMAN; INFLAMMATION; RED CELL DAMAGE ASSOCIATED MOLECULAR PATTERN; REVIEW; SICKLE CELL ANEMIA; VASCULITIS; ANIMAL; HEMOLYSIS; METABOLISM;

ALARMINS; ANIMALS; ERYTHROCYTES; HEMOGLOBINS; HEMOLYSIS; HUMANS; INFLAMMATION;

EID: 84973161446     PISSN: 10233830     EISSN: 1420908X     Source Type: Journal    
DOI: 10.1007/s00011-016-0955-9     Document Type: Review

References (160)

1. Quigley JG, Means RT Jr, Gçader B. The birth, life and death of red blood cells, erythropoiesis, the mature red blood cell and cell destruction. In: Greer JP, Arber DA, Glader B, List AF, Means Jr RT, Paraskevas F, et al., editors. Wintrobe’s clinical hematology. Philadelphia: Lippincott Williams & Wilkins, Wolters Kluwer; 2014. p. 83–124.
2. Means RT Jr, Glader B. Anemia: general considerations. In: Greer JP, Arber DA, Glader B, List AF, Means Jr RT, Paraskevas F, et al., editors. Wintrobe’s clinical hematology. Philadelphia: Lippincott Williams & Wilkins, Wolters Kluwer; 2014. p. 587–616.
3. Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic anemia. Am Fam Phys. 2004;69:2599–606.
4. Gram M, Dolberg Anderson U, Johansson ME, Edstrom-Hagerwall A, Larsson I, Jalmby M, et al. The human endogenous protection system against cell-free hemoglobin and heme is overwhelmed in preeclampsia and provides potential biomarkers and clinical indicators. PLoS One. 2015;10:e0138111.
5. Padmore R. Possible mechanisms for intravenous immunoglobulin-associated hemolysis: clues obtained from review of clinical case reports. Transfusion. 2015;55(Suppl 2):S59–64.
6. Barcellini W, Fattizzo B. Clinical applications of hemolytic markers in the differential diagnosis and management of hemolytic anemia. Dis Mark. 2015;2015:635670.
7. Kato GJ, McGowan V, Machado RF, Little JA, Jt Taylor, Morris CR, et al. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood. 2006;107:2279–85.
8. Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet. 2008;372:1411–26.
9. Schaer DJ, Buehler PW. Cell-free hemoglobin and its scavenger proteins: new disease models leading the way to targeted therapies. Cold Spring Harb Perspect Med. 2013;3:a013433.
10. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004;364:1343–60.
11. Conran N, Costa FF. Hemoglobin disorders and endothelial cell interactions. Clin Biochem. 2009;42:1824–38.
12. Hebbel RP, Vercellotti G, Nath KA. A systems biology consideration of the vasculopathy of sickle cell anemia: the need for multi-modality chemo-prophylaxsis. Cardiovasc Hematol Disord Drug Target. 2009;9:271–92.
13. MHO-F Steinberg K, Heeney MM. Clinical and pathophysiological aspects of sickle cell anemia. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, editors. Disorders of hemoglobin. Cambridge: Cambridge University Press; 2009.
14. Olivieri NF, Weatherall, D.J. Disorders of Hemoglobin. Chapter 17. New York:Cambridge University Press; 2009.
15. Atichartakarn V, Chuncharunee S, Archararit N, Udomsubpayakul U, Aryurachai K. Intravascular hemolysis, vascular endothelial cell activation and thrombophilia in splenectomized patients with hemoglobin E/beta-thalassemia disease. Acta Haematol. 2014;132:100–7.
16. Conran N. Intravascular hemolysis: a disease mechanism not to be ignored. Acta Haematol. 2014;132:97–9.
17. Conran N, Franco-Penteado CF, Costa FF. Newer aspects of the pathophysiology of sickle cell disease vaso-occlusion. Hemoglobin. 2009;33:1–16.
18. Almeida CB, Kato GJ, Conran N. Inflammation and sickle cell anemia. In: Costa FF, Conran N, editors. Sickle cell anemia: from basic science to clinical practice. Switzerland: Springer International; 2016. p. 177–211.
19. Hoppe CC. Inflammatory mediators of endothelial injury in sickle cell disease. Hematol Oncol Clin North Am. 2014;28:265–86.
20. Steinberg M. Overview of sickle cell anemia pathophysiology. In: Costa FF, Conran N, editors. Sickle cell anemia: from basic science to clinical practice. Switzerland: Springer International; 2016. p. 49–73.
21. Aggeli C, Antoniades C, Cosma C, Chrysohoou C, Tousoulis D, Ladis V, et al. Endothelial dysfunction and inflammatory process in transfusion-dependent patients with beta-thalassemia major. Int J Cardiol. 2005;105:80–4.
22. Musallam KM, Taher AT, Rachmilewitz EA. beta-thalassemia intermedia: a clinical perspective. Cold Spring Harb Perspect Med. 2012;2:a013482.
23. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293:1653–62.
24. Souza MC, Padua TA, Henriques MG. Endothelial-leukocyte interaction in severe malaria: beyond the brain. Mediat Inflamm. 2015;2015:168937.
25. Schaer DJ, Vinchi F, Ingoglia G, Tolosano E, Buehler PW. Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development. Front Physiol. 2014;5:415.
26. Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO 3rd, Schechter AN, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med. 2002;8:1383–9.
27. Schaer DJ, Buehler PW, Alayash AI, Belcher JD, Vercellotti GM. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood. 2013;121:1276–84.
28. Stamler JS, Jia L, Eu JP, McMahon TJ, Demchenko IT, Bonaventura J, et al. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science. 1997;276:2034–7.
29. Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003;9:1498–505.
30. Gladwin MT, Crawford JH, Patel RP. The biochemistry of nitric oxide, nitrite, and hemoglobin: role in blood flow regulation. Free Radic Biol Med. 2004;36:707–17.
31. Helms CC, Marvel M, Zhao W, Stahle M, Vest R, Kato GJ, et al. Mechanisms of hemolysis-associated platelet activation. J Thromb Haemost. 2013;11:2148–54.
32. Almeida CB, Souza LE, Leonardo FC, Costa FT, Werneck CC, Covas DT, et al. Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea. Blood. 2015;126:711–20.
33. Belcher JD, Chen C, Nguyen J, Milbauer L, Abdulla F, Alayash AI, et al. Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood. 2014;123:377–90.
34. Dutra FF, Alves LS, Rodrigues D, Fernandez PL, de Oliveira RB, Golenbock DT, et al. Hemolysis-induced lethality involves inflammasome activation by heme. Proc Natl Acad Sci USA. 2014;111:E4110–8.
35. Dutra FF, Bozza MT. Heme on innate immunity and inflammation. Front Pharmacol. 2014;5:115.
36. Porto BN, Alves LS, Fernandez PL, Dutra TP, Figueiredo RT, Graca-Souza AV, et al. Heme induces neutrophil migration and reactive oxygen species generation through signaling pathways characteristic of chemotactic receptors. J Biol Chem. 2007;282:24430–6.
37. Jeney V, Balla J, Yachie A, Varga Z, Vercellotti GM, Eaton JW, et al. Pro-oxidant and cytotoxic effects of circulating heme. Blood. 2002;100:879–87.
38. Figueiredo RT, Fernandez PL, Mourao-Sa DS, Porto BN, Dutra FF, Alves LS, et al. Characterization of heme as activator of toll-like receptor 4. J Biol Chem. 2007;282:20221–9.
39. Wagener FA, Volk HD, Willis D, Abraham NG, Soares MP, Adema GJ, et al. Different faces of the heme-heme oxygenase system in inflammation. Pharmacol Rev. 2003;55:551–71.
40. Hunt RC, Handy I, Smith A. Heme-mediated reactive oxygen species toxicity to retinal pigment epithelial cells is reduced by hemopexin. J Cell Physiol. 1996;168:81–6.
41. Yamada N, Yamaya M, Okinaga S, Lie R, Suzuki T, Nakayama K, et al. Protective effects of heme oxygenase-1 against oxidant-induced injury in the cultured human tracheal epithelium. Am J Respir Cell Mol Biol. 1999;21:428–35.
42. Fernandez PL, Dutra FF, Alves L, Figueiredo RT, Mourao-Sa D, Fortes GB, et al. Heme amplifies the innate immune response to microbial molecules through spleen tyrosine kinase (Syk)-dependent reactive oxygen species generation. J Biol Chem. 2010;285:32844–51.
43. Setty BN, Betal SG, Zhang J, Stuart MJ. Heme induces endothelial tissue factor expression: potential role in hemostatic activation in patients with hemolytic anemia. J Thromb Haemost. 2008;6:2202–9.
44. Camus SM, De Moraes JA, Bonnin P, Abbyad P, Le Jeune S, Lionnet F, et al. Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vaso-occlusions in sickle cell disease. Blood. 2015;125:3805–14.
45. Sprague RS, Stephenson AH, Ellsworth ML. Red not dead: signaling in and from erythrocytes. Trend Endocrinol Metab. 2007;18:350–5.
46. Ramdani G, Langsley G. ATP, an extracellular signaling molecule in red blood cells: a messenger for malaria? Biomed J. 2014;37:284–92.
47. Nur E, Biemond BJ, Otten HM, Brandjes DP, Schnog JJ, Group CS. Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management. Am J Hematol. 2011;86:484–9.
48. Sprague RS, Ellsworth ML. Erythrocyte-derived ATP and perfusion distribution: role of intracellular and intercellular communication. Microcirculation. 2012;19:430–9.
49. Gorman MW, Feigl EO, Buffington CW. Human plasma ATP concentration. Clin Chem. 2007;53:318–25.
50. Idzko M, Ferrari D, Eltzschig HK. Nucleotide signalling during inflammation. Nature. 2014;509:310–7.
51. Idzko M, Ferrari D, Riegel AK, Eltzschig HK. Extracellular nucleotide and nucleoside signaling in vascular and blood disease. Blood. 2014;124:1029–37.
52. Sumi Y, Woehrle T, Chen Y, Bao Y, Li X, Yao Y, et al. Plasma ATP is required for neutrophil activation in a mouse sepsis model. Shock. 2014;42:142–7.
53. Lecut C, Frederix K, Johnson DM, Deroanne C, Thiry M, Faccinetto C, et al. P2X1 ion channels promote neutrophil chemotaxis through rho kinase activation. J Immunol. 2009;183:2801–9.
54. Bours MJ, Dagnelie PC, Giuliani AL, Wesselius A, Di Virgilio F. P2 receptors and extracellular ATP: a novel homeostatic pathway in inflammation. Front Biosci (Schol Ed). 2011;3:1443–56.
55. Sluyter R. P2X and P2Y receptor signaling in red blood cells. Front Mol Biosci. 2015;2:60.
56. Zhang Y, Dai Y, Wen J, Zhang W, Grenz A, Sun H, et al. Detrimental effects of adenosine signaling in sickle cell disease. Nat Med. 2011;17:79–86.
57. Field JJ, Nathan DG, Linden J. The role of adenosine signaling in sickle cell therapeutics. Hematol Oncol Clin North Am. 2014;28:287–99.
58. Gromov PS, Celis JE. Identification of two molecular chaperons (HSX70, HSC70) in mature human erythrocytes. Exp Cell Res. 1991;195:556–9.
59. Kim JY, Yenari MA. The immune modulating properties of the heat shock proteins after brain injury. Anat Cell Biol. 2013;46:1–7.
60. Jheng HF, Tsai PJ, Chuang YL, Shen YT, Tai TA, Chen WC, et al. Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy. Dis Model Mech. 2015;8:1311–21.
61. Molvarec A, Tamasi L, Losonczy G, Madach K, Prohaszka Z, Rigo J Jr. Circulating heat shock protein 70 (HSPA1A) in normal and pathological pregnancies. Cell Stress Chaperones. 2010;15:237–47.
62. Bhattacharya D, Saha S, Basu S, Chakravarty S, Chakravarty A, Banerjee D, et al. Differential regulation of redox proteins and chaperones in HbEbeta-thalassemia erythrocyte proteome. Proteom Clin Appl. 2010;4:480–8.
63. Adewoye AH, Klings ES, Farber HW, Palaima E, Bausero MA, McMahon L, et al. Sickle cell vaso-occlusive crisis induces the release of circulating serum heat shock protein-70. Am J Hematol. 2005;78:240–2.
64. Lott JM, Sumpter TL, Turnquist HR. New dog and new tricks: evolving roles for IL-33 in type 2 immunity. J Leukoc Biol. 2015;97:1037–48.
65. Wei J, Zhao J, Schrott V, Zhang Y, Gladwin M, Bullock G, et al. Red blood cells store and release interleukin-33. J Investig Med. 2015;63:806–10.
66. Bu X, Zhang T, Wang C, Ren T, Wen Z. IL-33 reflects dynamics of disease activity in patients with autoimmune hemolytic anemia by regulating autoantibody production. J Transl Med. 2015;13:381.
67. Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity. 2015;42:1005–19.
68. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7.
69. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401–14.
70. Pazmandi K, Agod Z, Kumar BV, Szabo A, Fekete T, Sogor V, et al. Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells. Free Radic Biol Med. 2014;77:281–90.
71. Lee YL, King MB, Gonzalez RP, Brevard SB, Frotan MA, Gillespie MN, et al. Blood transfusion products contain mitochondrial DNA damage-associated molecular patterns: a potential effector of transfusion-related acute lung injury. J Surg Res. 2014;191:286–9.
72. Billich A, Winkler G, Aschauer H, Rot A, Peichl P. Presence of cyclophilin a in synovial fluids of patients with rheumatoid arthritis. J Exp Med. 1997;185:975–80.
73. Tegeder I, Schumacher A, John S, Geiger H, Geisslinger G, Bang H, et al. Elevated serum cyclophilin levels in patients with severe sepsis. J Clin Immunol. 1997;17:380–6.
74. Kim H, Kim WJ, Jeon ST, Koh EM, Cha HS, Ahn KS, et al. Cyclophilin a may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages. Clin Immunol. 2005;116:217–24.
75. Dear JW, Simpson KJ, Nicolai MP, Catterson JH, Street J, Huizinga T, et al. Cyclophilin A is a damage-associated molecular pattern molecule that mediates acetaminophen-induced liver injury. J Immunol. 2011;187:3347–52.
76. Kakhniashvili DG, Bulla LA Jr, Goodman SR. The human erythrocyte proteome: analysis by ion trap mass spectrometry. Mol Cell Proteom. 2004;3:501–9.
77. Pasini EM, Kirkegaard M, Mortensen P, Lutz HU, Thomas AW, Mann M. In-depth analysis of the membrane and cytosolic proteome of red blood cells. Blood. 2006;108:791–801.
78. Pruchniak MP, Kotula I, Manda-Handzlik A. Neutrophil extracellular traps (Nets) impact upon autoimmune disorders. Cent Eur J Immunol. 2015;40:217–24.
79. Grayson PC, Kaplan MJ. At the Bench: Neutrophil extracellular traps (NETs) highlight novel aspects of innate immune system involvement in autoimmune diseases. J Leukoc Biol. 2016;99:253–64.
80. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176:231–41.
81. Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, Henriques-Normark B. An endonuclease allows streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr Biol. 2006;16:401–7.
82. Yu Y, Su K. Neutrophil extracellular traps and systemic lupus erythematosus. J Clin Cell Immunol. 2013;4:139
83. Doring Y, Manthey HD, Drechsler M, Lievens D, Megens RT, Soehnlein O, et al. Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation. 2012;125:1673–83.
84. Schimmel M, Nur E, Biemond BJ, van Mierlo GJ, Solati S, Brandjes DP, et al. Nucleosomes and neutrophil activation in sickle cell disease painful crisis. Haematologica. 2013;98:1797–803.
85. Thomas GM, Carbo C, Curtis BR, Martinod K, Mazo IB, Schatzberg D, et al. Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood. 2012;119:6335–43.
86. Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007;21:37–47.
87. Peters AL, van Hezel ME, Juffermans NP, Vlaar AP. Pathogenesis of non-antibody mediated transfusion-related acute lung injury from bench to bedside. Blood Rev. 2015;29:51–61.
88. Kono M, Saigo K, Takagi Y, Takahashi T, Kawauchi S, Wada A, et al. Heme-related molecules induce rapid production of neutrophil extracellular traps. Transfusion. 2014;54:2811–9.
89. Kono M, Saigo K, Takagi Y, Kawauchi S, Wada A, Hashimoto M, et al. Morphological and flow-cytometric analysis of haemin-induced human neutrophil activation: implications for transfusion-related acute lung injury. Blood Transfus. 2013;11:53–60.
90. Graca-Souza AV, Arruda MA, de Freitas MS, Barja-Fidalgo C, Oliveira PL. Neutrophil activation by heme: implications for inflammatory processes. Blood. 2002;99:4160–5.
91. Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood. 2014;123:3818–27.
92. Tran H, Jha R, Nguyen J, Jarrett S, Rodriguez J, Mittal A, et al. Hemin-induced mast cell-extracellular traps impart resistance to therapy in a sickle microenvironment. Blood. 2015;126:Abstract 3385.
93. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511.
94. Mariathasan S, Monack DM. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol. 2007;7:31–40.
95. Kang JY, Lee JO. Structural biology of the toll-like receptor family. Annu Rev Biochem. 2011;80:917–41.
96. Goulopoulou S, McCarthy CG, Webb RC. Toll-like receptors in the vascular system: sensing the dangers within. Pharmacol Rev. 2016;68:142–67.
97. Wang Y, Song E, Bai B, Vanhoutte PM. Toll-like receptors mediating vascular malfunction: lessons from receptor subtypes. Pharmacol Ther. 2016;158:91–100.
98. Bellocchio S, Moretti S, Perruccio K, Fallarino F, Bozza S, Montagnoli C, et al. TLRs govern neutrophil activity in aspergillosis. J Immunol. 2004;173:7406–15.
99. Belcher JD, Nath KA, Vercellotti GM. Vasculotoxic and Proinflammatory Effects of Plasma Heme: Cell Signaling and Cytoprotective Responses. ISRN Oxidative Med. 2013;2013:831596.
100. Lin S, Yin Q, Zhong Q, Lv FL, Zhou Y, Li JQ, et al. Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage. J Neuroinflamm. 2012;9:46.
101. Kwon MS, Woo SK, Kurland DB, Yoon SH, Palmer AF, Banerjee U, et al. Methemoglobin is an endogenous toll-like receptor 4 ligand-relevance to subarachnoid hemorrhage. Int J Mol Sci. 2015;16:5028–46.
102. Fortes GB, Alves LS, de Oliveira R, Dutra FF, Rodrigues D, Fernandez PL, et al. Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production. Blood. 2012;119:2368–75.
103. Teng W, Wang L, Xue W, Guan C. Activation of TLR4-mediated NFkappaB signaling in hemorrhagic brain in rats. Mediat Inflamm. 2009;2009:473276.
104. Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014;1843:2563–82.
105. Lanaro C, Franco-Penteado CF, Albuqueque DM, Saad ST, Conran N, Costa FF. Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy. J Leukoc Biol. 2009;85:235–42.
106. Pathare A, Al Kindi S, Alnaqdy AA, Daar S, Knox-Macaulay H, Dennison D. Cytokine profile of sickle cell disease in Oman. Am J Hematol. 2004;77:323–8.
107. Qari MH, Dier U, Mousa SA. Biomarkers of inflammation, growth factor, and coagulation activation in patients with sickle cell disease. Clin Appl Thromb Hemost. 2012;18:195–200.
108. Randall LM, Engwerda CR. TNF family members and malaria: old observations, new insights and future directions. Exp Parasitol. 2010;126:326–31.
109. Ghosh S, Adisa OA, Chappa P, Tan F, Jackson KA, Archer DR, et al. Extracellular hemin crisis triggers acute chest syndrome in sickle mice. J Clin Invest. 2013;123:4809–20.
110. van Beers EJ, Yang Y, Raghavachari N, Tian X, Allen DT, Nichols JS, et al. Iron, inflammation, and early death in adults with sickle cell disease. Circ Res. 2015;116:298–306.
111. Vincent L, Vang D, Nguyen J, Gupta M, Luk K, Ericson ME, et al. Mast cell activation contributes to sickle cell pathobiology and pain in mice. Blood. 2013;122:1853–62.
112. Pamplona A, Hanscheid T, Epiphanio S, Mota MM, Vigario AM. Cerebral malaria and the hemolysis/methemoglobin/heme hypothesis: shedding new light on an old disease. Int J Biochem Cell Biol. 2009;41:711–6.
113. Dickinson-Copeland CM, Wilson NO, Liu M, Driss A, Salifu H, Adjei AA, et al. Heme-mediated induction of CXCL10 and depletion of CD34+ progenitor cells is toll-like receptor 4 dependent. PLoS One. 2015;10:e0142328.
114. Zhao H, Perez JS, Lu K, George AJ, Ma D. Role of toll-like receptor-4 in renal graft ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2014;306:F801–11.
115. Kwok YH, Tuke J, Nicotra LL, Grace PM, Rolan PE, Hutchinson MR. TLR 2 and 4 responsiveness from isolated peripheral blood mononuclear cells from rats and humans as potential chronic pain biomarkers. PLoS One. 2013;8:e77799.
116. Kato J, Svensson CI. Role of extracellular damage-associated molecular pattern molecules (DAMPs) as mediators of persistent pain. Prog Mol Biol Transl Sci. 2015;131:251–79.
117. Kohli DR, Li Y, Khasabov SG, Gupta P, Kehl LJ, Ericson ME, et al. Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids. Blood. 2010;116:456–65.
118. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.
119. Krishnan SM, Sobey CG, Latz E, Mansell A, Drummond GR. IL-1beta and IL-18: inflammatory markers or mediators of hypertension? Br J Pharmacol. 2014;171:5589–602.
120. Zhong Y, Kinio A, Saleh M. Functions of NOD-like receptors in human diseases. Front Immunol. 2013;4:333.
121. Ozaki E, Campbell M, Doyle SL. Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives. J Inflamm Res. 2015;8:15–27.
122. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–87.
123. Dunne A. Inflammasome activation: from inflammatory disease to infection. Biochem Soc Trans. 2011;39:669–73.
124. Man SM, Kanneganti TD. Regulation of inflammasome activation. Immunol Rev. 2015;265:6–21.
125. Vanaja SK, Rathinam VA, Fitzgerald KA. Mechanisms of inflammasome activation: recent advances and novel insights. Trend Cell Biol. 2015;25:308–15.
126. Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM, Nunez G. K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 2013;38:1142–53.
127. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221–5.
128. Harijith A, Ebenezer DL, Natarajan V. Reactive oxygen species at the crossroads of inflammasome and inflammation. Front Physiol. 2014;5:352.
129. Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A, Engels G, et al. The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat Immunol. 2014;15:727–37.
130. Kahlenberg JM, Carmona-Rivera C, Smith CK, Kaplan MJ. Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol. 2013;190:1217–26.
131. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. Inflammation. neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science. 2015;349:316–20.
132. Li Q, Fu W, Yao J, Ji Z, Wang Y, Zhou Z, et al. Heme induces IL-1beta secretion through activating NLRP3 in kidney inflammation. Cell Biochem Biophys. 2014;69:495–502.
133. Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, et al. Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem. 2001;276:125–32.
134. Quaye IK. Haptoglobin, inflammation and disease. Trans R Soc Trop Med Hyg. 2008;102:735–42.
135. Mehta NU, Reddy ST. Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases. Curr Opin Lipidol. 2015;26:384–7.
136. Ijas P, Saksi J, Soinne L, Tuimala J, Jauhiainen M, Jula A, et al. Haptoglobin 2 allele associates with unstable carotid plaque and major cardiovascular events. Atherosclerosis. 2013;230:228–34.
137. Suleiman M, Kapeliovich MR, Roguin A, Aronson D, Meisel SR, Shochat M, et al. Haptoglobin type and 30-day mortality in diabetic individuals presenting with acute myocardial infarction. Diabetes Care. 2003;26:2699–700.
138. Lipiski M, Deuel JW, Baek JH, Engelsberger WR, Buehler PW, Schaer DJ. Human Hp1-1 and Hp2-2 phenotype-specific haptoglobin therapeutics are both effective in vitro and in guinea pigs to attenuate hemoglobin toxicity. Antioxid Redox Signal. 2013;19:1619–33.
139. Mollan TL, Jia Y, Banerjee S, Wu G, Kreulen RT, Tsai AL, et al. Redox properties of human hemoglobin in complex with fractionated dimeric and polymeric human haptoglobin. Free Radic Biol Med. 2014;69:265–77.
140. Purushothaman M, Krishnan P, Purushothaman KR, Baber U, Tarricone A, Perez JS, et al. Genotype-dependent impairment of hemoglobin clearance increases oxidative and inflammatory response in human diabetic atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:2769–75.
141. Landis RC, Philippidis P, Domin J, Boyle JJ, Haskard DO. Haptoglobin genotype-dependent anti-inflammatory signaling in cd163(+) macrophages. Int J Inflamm. 2013;2013:980327.
142. Levy AP, Purushothaman KR, Levy NS, Purushothaman M, Strauss M, Asleh R, et al. Downregulation of the hemoglobin scavenger receptor in individuals with diabetes and the Hp 2-2 genotype: implications for the response to intraplaque hemorrhage and plaque vulnerability. Circ Res. 2007;101:106–10.
143. Ragab SM, Safan MA, Badr EA, Ebeid OM. Haptoglobin genotypes polymorphism as a risk factor for subclinical atherosclerosis in beta-thalassemia major children; a single center Egyptian study. Hematology. 2015;20:477–86.
144. Pierrot-Gallo BS, Vicari P, Matsuda SS, Adegoke SA, Mecabo G, Figueiredo MS. Haptoglobin gene polymorphisms and interleukin-6 and -8 levels in patients with sickle cell anemia. Rev Bras Hematol Hemoter. 2015;37:329–35.
145. Atkinson SH, Mwangi TW, Uyoga SM, Ogada E, Macharia AW, Marsh K, et al. The haptoglobin 2-2 genotype is associated with a reduced incidence of plasmodium falciparum malaria in children on the coast of Kenya. Clin Infect Dis. 2007;44:802–9.
146. Bienzle U, Eggelte TA, Adjei LA, Dietz E, Ehrhardt S, Cramer JP, et al. Limited influence of haptoglobin genotypes on severe malaria in Ghanaian children. Trop Med Int Health. 2005;10:668–71.
147. Quaye IK, Ekuban FA, Goka BQ, Adabayeri V, Kurtzhals JA, Gyan B, et al. Haptoglobin 1-1 is associated with susceptibility to severe plasmodium falciparum malaria. Trans R Soc Trop Med Hyg. 2000;94:216–9.
148. Perdijk O, Arama C, Giusti P, Maiga B, Troye-Blomberg M, Dolo A, et al. Haptoglobin phenotype prevalence and cytokine profiles during plasmodium falciparum infection in dogon and fulani ethnic groups living in Mali. Malar J. 2013;12:432.
149. Tolosano E, Altruda F. Hemopexin: structure, function, and regulation. DNA Cell Biol. 2002;21:297–306.
150. Karnaukhova K, Rutardottir S, Rajabi M, Wester Rosenlof L, Alayash AI, Akerstrom B. Characterization of heme binding to recombinant alpha1-microglobulin. Front Physiol. 2014;5:465.
151. Olsson MG, Olofsson T, Tapper H, Akerstrom B. The lipocalin alpha1-microglobulin protects erythroid K562 cells against oxidative damage induced by heme and reactive oxygen species. Free Radic Res. 2008;42:725–36.
152. Boyle JJ, Johns M, Lo J, Chiodini A, Ambrose N, Evans PC, et al. Heme induces heme oxygenase 1 via Nrf2: role in the homeostatic macrophage response to intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2011;31:2685–91.
153. Chintagari NR, Nguyen J, Belcher JD, Vercellotti GM, Alayash AI. Haptoglobin attenuates hemoglobin-induced heme oxygenase-1 in renal proximal tubule cells and kidneys of a mouse model of sickle cell disease. Blood Cells Mol Dis. 2015;54:302–6.
154. Ragab SM, Safan MA, Badr EA. Study of serum haptoglobin level and its relation to erythropoietic activity in beta thalassemia children. Mediterr J Hematol Infect Dis. 2015;7:e2015019.
155. Muller-Eberhard U, Javid J, Liem HH, Hanstein A, Hanna M. Plasma concentrations of hemopexin, haptoglobin and heme in patients with various hemolytic diseases. Blood. 1968;32:811–5.
156. Bourantas KL, Dalekos GN, Makis A, Chaidos A, Tsiara S, Mavridis A. Acute phase proteins and interleukins in steady state sickle cell disease. Eur J Haematol. 1998;61:49–54.
157. Foidart M, Liem HH, Adornato BT, Engel WK, Muller-Eberhard U. Hemopexin metabolism in patients with altered serum levels. J Lab Clin Med. 1983;102:838–46.
158. Wintrobe’s Clinical Hematology. In: Greer JP, Arber DA, Glader B, List AF, Means Jr RT, Paraskevas F, et al., editors. Philadelphia: Lippincott Williams & Wilkins, Wolters Kluwer 2014.
159. Costa FF, Fertrin KY, Conran N. Síndrome hemolítica. Fisiopatologia e Clínica. In: Zago MA, Falcão RP, Pasquini R, editors. Tratado de Hematologia. São Paulo: Atheneu 2013.
160. Costa FF, Conran N, K.Y. F. Anemia Falciforme. In: Zago MA, Falcão RP, Pasquini R, editors. Tratado de Hematologia 2013.