Advertisement

Extracellular Heat Shock Proteins as Stress Communication Signals

  • Antonio De Maio
Chapter

Abstract

Intercellular communication is a fundamental process necessary to maintain homeostasis and to mount an orchestrated response to stress. Although heat shock proteins (HSP) play a critical role by participating in the repair of damaged products as a result of the stress in the intracellular milieu, it is now evident that they play an alternative role when they escape from the cells and are placed in circulation, participating in a systemic stress response. Extracellular HSP appear as signaling molecules involved in intercellular communication during stress conditions. They have been found to modulate the function of many target cells. Moreover, extracellular HSP have been detected in several biological fluids, particularly from patients suffering from a large number of maladies. Extracellular HSP are released by many cell types and by several mechanisms, including passive dissemination after necrosis and active export by a nonclassical secretory pathway. Among several potential mechanisms for the export of HSP, their release associated with extracellular vesicles has gained increasing support. The appearance of extracellular vesicles containing HSP emerges as a new form of cellular communication during stress conditions directed at avoiding the propagation of the insult.

Keywords

Heat shock proteins Cellular communication Extracellular vesicles Stress Signaling 

Notes

Acknowledgments

This work was supported by the National Institutes of Health, grant number GM R01 09845.

References

  1. 1.
    Ahmed KA, Xiang J (2011) Mechanisms of cellular communication through intercellular protein transfer. J Cell Mol Med 15:1458–1473PubMedCrossRefGoogle Scholar
  2. 2.
    Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML (1999) The immunological synapse: a molecular machine controlling T cell activation. Science 285:221–227PubMedCrossRefGoogle Scholar
  3. 3.
    Davis DM (2007) Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response. Nat Rev Immunol 7:238–243PubMedCrossRefGoogle Scholar
  4. 4.
    Arispe N, Doh M, De Maio A (2002) Lipid interaction differentiates the constitutive and stress-induced heat shock proteins Hsc70 and Hsp70. Cell Stress Chaperones 7:330–338PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593PubMedCrossRefGoogle Scholar
  6. 6.
    De Maio A (2011) Extracellular heat shock proteins, cellular export vesicles, and the stress observation system: a form of communication during injury, infection, and cell damage. It is never known how far a controversial finding will go! Dedicated to Ferruccio Ritossa. Cell Stress Chaperones 16:235–249PubMedCrossRefGoogle Scholar
  7. 7.
    Mulcahy LA, Pink RC, Carter DR (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 3.  https://doi.org/10.3402/jev.v3.24641
  8. 8.
    Ritossa FM (1962) A new puffing pattern induced by temperature shock and DNP in drosophila. Cell Mol Life Sci 18:571–573CrossRefGoogle Scholar
  9. 9.
    Tissieres A, Mitchell HK, Tracy UM (1974) Protein synthesis in salivary glands of Drosophila Melanogaster: relation to chromosome puffs. J Mol Biol 84:389–398PubMedCrossRefGoogle Scholar
  10. 10.
    De Maio A (1999) Heat shock proteins: facts, thoughts, and dreams. Shock 11:1–12PubMedCrossRefGoogle Scholar
  11. 11.
    Hartl FU, Hayer-Hartl M (2009) Converging concepts of protein folding in vitro and in vivo. Nat Struct Mol Biol 16:574–581PubMedCrossRefGoogle Scholar
  12. 12.
    Lindquist S, Craig EA (1988) The heat-shock proteins. Annu Rev Genet 22:631–677PubMedCrossRefGoogle Scholar
  13. 13.
    Becker T, Hartl FU, Wieland F (2002) CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol 158:1277–1285PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, Cheetham ME, Chen B, Hightower LE (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14:105–111PubMedCrossRefGoogle Scholar
  15. 15.
    Tytell M, Greenberg SG, Lasek RJ (1986) Heat shock-like protein is transferred from glia to axon. Brain Res 363:161–164PubMedCrossRefGoogle Scholar
  16. 16.
    Hightower LE, Guidon PT Jr (1989) Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins. J Cell Physiol 138:257–266PubMedCrossRefGoogle Scholar
  17. 17.
    Liao DF, Jin ZG, Baas AS, Daum G, Gygi SP, Aebersold R, Berk BC (2000) Purification and identification of secreted oxidative stress-induced factors from vascular smooth muscle cells. J Biol Chem 275:189–196PubMedCrossRefGoogle Scholar
  18. 18.
    Suzuki S, Kulkarni AB (2010) Extracellular heat shock protein HSP90beta secreted by MG63 osteosarcoma cells inhibits activation of latent TGF-beta1. Biochem Biophys Res Commun 398:525–531PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Pilzer D, Fishelson Z (2005) Mortalin/GRP75 promotes release of membrane vesicles from immune attacked cells and protection from complement-mediated lysis. Int Immunol 17:1239–1248PubMedCrossRefGoogle Scholar
  20. 20.
    Delpino A, Castelli M (2002) The 78 kDa glucose-regulated protein (GRP78/BIP) is expressed on the cell membrane, is released into cell culture medium and is also present in human peripheral circulation. Biosci Rep 22:407–420PubMedCrossRefGoogle Scholar
  21. 21.
    Kern J, Untergasser G, Zenzmaier C, Sarg B, Gastl G, Gunsilius E, Steurer M (2009) GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib. Blood 114:3960–3967PubMedCrossRefGoogle Scholar
  22. 22.
    Evdokimovskaya Y, Skarga Y, Vrublevskaya V, Morenkov O (2012) Release of the glucose-regulated protein 94 by baby hamster kidney cells. Cell Biochem Funct 30:558–562PubMedCrossRefGoogle Scholar
  23. 23.
    Henderson B, Pockley AG (2012) Proteotoxic stress and circulating cell stress proteins in the cardiovascular diseases. Cell Stress Chaperones 17:303–311PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Nafar F, Williams JB, Mearow KM (2016) Astrocytes release HspB1 in response to amyloid-beta exposure in vitro. J Alzheimers Dis 49:251–263PubMedCrossRefGoogle Scholar
  25. 25.
    Zuo D, Yu X, Guo C, Yi H, Chen X, Conrad DH, Guo TL, Chen Z, Fisher PB, Subjeck JR, Wang XY (2012) Molecular chaperoning by glucose-regulated protein 170 in the extracellular milieu promotes macrophage-mediated pathogen sensing and innate immunity. FASEB J 26:1493–1505PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435–442PubMedCrossRefGoogle Scholar
  27. 27.
    Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H (2002) HSP70 as endogenous stimulus of the toll/interleukin-1 receptor signal pathway. J Biol Chem 277:15107–15112PubMedCrossRefGoogle Scholar
  28. 28.
    Vega VL, Rodriguez-Silva M, Frey T, Gehrmann M, Diaz JC, Steinem C, Multhoff G, Arispe N, De Maio A (2008) Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol 180:4299–4307PubMedCrossRefGoogle Scholar
  29. 29.
    Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 12:1539–1546PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Gastpar R, Gross C, Rossbacher L, Ellwart J, Riegger J, Multhoff G (2004) The cell surface-localized heat shock protein 70 epitope TKD induces migration and cytolytic activity selectively in human NK cells. J Immunol 172:972–980PubMedCrossRefGoogle Scholar
  31. 31.
    Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, Multhoff G (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65:5238–5247PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Aneja R, Odoms K, Dunsmore K, Shanley TP, Wong HR (2006) Extracellular heat shock protein-70 induces endotoxin tolerance in THP-1 cells. J Immunol 177:7184–7192PubMedCrossRefGoogle Scholar
  33. 33.
    Abboud PA, Lahni PM, Page K, Giuliano JS Jr, Harmon K, Dunsmore KE, Wong HR, Wheeler DS (2008) The role of endogenously produced extracellular hsp72 in mononuclear cell reprogramming. Shock 30:285–292PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Ortega E, Hinchado MD, Martin-Cordero L, Asea A (2009) The effect of stress-inducible extracellular Hsp72 on human neutrophil chemotaxis: a role during acute intense exercise. Stress 12:240–249PubMedCrossRefGoogle Scholar
  35. 35.
    Ortega E, Giraldo E, Hinchado MD, Martinez M, Ibanez S, Cidoncha A, Collazos ME, Garcia JJ (2006) Role of Hsp72 and norepinephrine in the moderate exercise-induced stimulation of neutrophils’ microbicide capacity. Eur J Appl Physiol 98:250–255PubMedCrossRefGoogle Scholar
  36. 36.
    Wang R, Kovalchin JT, Muhlenkamp P, Chandawarkar RY (2006) Exogenous heat shock protein 70 binds macrophage lipid raft microdomain and stimulates phagocytosis, processing, and MHC-II presentation of antigens. Blood 107:1636–1642PubMedCrossRefGoogle Scholar
  37. 37.
    Kovalchin JT, Wang R, Wagh MS, Azoulay J, Sanders M, Chandawarkar RY (2006) In vivo delivery of heat shock protein 70 accelerates wound healing by up-regulating macrophage-mediated phagocytosis. Wound Repair Regen 14:129–137PubMedCrossRefGoogle Scholar
  38. 38.
    Lopes RL, Borges TJ, Araujo JF, Pinho NG, Bergamin LS, Battastini AM, Muraro SP, Souza AP, Zanin RF, Bonorino C (2014) Extracellular mycobacterial DnaK polarizes macrophages to the M2-like phenotype. PLoS One 9:e113441PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Borges TJ, Lopes RL, Pinho NG, Machado FD, Souza AP, Bonorino C (2013) Extracellular Hsp70 inhibits pro-inflammatory cytokine production by IL-10 driven down-regulation of C/EBPbeta and C/EBPdelta. Int J Hyperth 29:455–463CrossRefGoogle Scholar
  40. 40.
    Takeuchi T, Suzuki M, Fujikake N, Popiel HA, Kikuchi H, Futaki S, Wada K, Nagai Y (2015) Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level. Proc Natl Acad Sci U S A 112:E2497–E2506PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Pockley AG, Muthana M, Calderwood SK (2008) The dual immunoregulatory roles of stress proteins. Trends Biochem Sci 33:71–79PubMedCrossRefGoogle Scholar
  42. 42.
    Oura J, Tamura Y, Kamiguchi K, Kutomi G, Sahara H, Torigoe T, Himi T, Sato N (2011) Extracellular heat shock protein 90 plays a role in translocating chaperoned antigen from endosome to proteasome for generating antigenic peptide to be cross-presented by dendritic cells. Int Immunol 23:223–237PubMedCrossRefGoogle Scholar
  43. 43.
    van Noort JM, Bsibsi M, Nacken P, Gerritsen WH, Amor S (2012) The link between small heat shock proteins and the immune system. Int J Biochem Cell Biol 44:1670–1679PubMedCrossRefGoogle Scholar
  44. 44.
    Li W, Li Y, Guan S, Fan J, Cheng CF, Bright AM, Chinn C, Chen M, Woodley DT (2007) Extracellular heat shock protein-90alpha: linking hypoxia to skin cell motility and wound healing. EMBO J 26:1221–1233PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Bhatia A, O'Brien K, Chen M, Woodley DT, Li W (2016) Keratinocyte-secreted heat shock protein-90alpha: leading wound reepithelialization and closure. Adv Wound Care (New Rochelle) 5:176–184CrossRefGoogle Scholar
  46. 46.
    Mathur S, Walley KR, Wang Y, Indrambarya T, Boyd JH (2011) Extracellular heat shock protein 70 induces cardiomyocyte inflammation and contractile dysfunction via TLR2. Circ J 75:2445–2452PubMedCrossRefGoogle Scholar
  47. 47.
    Thuringer D, Berthenet K, Cronier L, Jego G, Solary E, Garrido C (2015) Oncogenic extracellular HSP70 disrupts the gap-junctional coupling between capillary cells. Oncotarget 6:10267–10283PubMedPubMedCentralGoogle Scholar
  48. 48.
    Calderwood SK, Gong J, Murshid A (2016) Extracellular HSPs: the complicated roles of extracellular HSPs in immunity. Front Immunol 7:159PubMedPubMedCentralGoogle Scholar
  49. 49.
    Binder RJ, Han DK, Srivastava PK (2000) CD91: a receptor for heat shock protein gp96. Nat Immunol 1:151–155PubMedCrossRefGoogle Scholar
  50. 50.
    Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14:303–313PubMedCrossRefGoogle Scholar
  51. 51.
    Wang Y, Kelly CG, Karttunen JT, Whittall T, Lehner PJ, Duncan L, MacAry P, Younson JS, Singh M, Oehlmann W, Cheng G, Bergmeier L, Lehner T (2001) CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 15:971–983PubMedCrossRefGoogle Scholar
  52. 52.
    Facciponte JG, Wang XY, Subjeck JR (2007) Hsp110 and Grp170, members of the Hsp70 superfamily, bind to scavenger receptor-a and scavenger receptor expressed by endothelial cells-I. Eur J Immunol 37:2268–2279PubMedCrossRefGoogle Scholar
  53. 53.
    Theriault JR, Adachi H, Calderwood SK (2006) Role of scavenger receptors in the binding and internalization of heat shock protein 70. J Immunol 177:8604–8611PubMedCrossRefGoogle Scholar
  54. 54.
    Yang S, Vigerust DJ, Shepherd VL (2013) Interaction of members of the heat shock protein-70 family with the macrophage mannose receptor. J Leukoc Biol 93:529–536PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Alard JE, Hillion S, Guillevin L, Saraux A, Pers JO, Youinou P, Jamin C (2011) Autoantibodies to endothelial cell surface ATP synthase, the endogenous receptor for hsp60, might play a pathogenic role in vasculatides. PLoS One 6:e14654PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Fong JJ, Sreedhara K, Deng L, Varki NM, Angata T, Liu Q, Nizet V, Varki A (2015) Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14. EMBO J 34:2775–2788PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Gehrmann M, Liebisch G, Schmitz G, Anderson R, Steinem C, De Maio A, Pockley G, Multhoff G (2008) Tumor-specific Hsp70 plasma membrane localization is enabled by the glycosphingolipid Gb3. PLoS One 3:e1925PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Sugawara S, Kawano T, Omoto T, Hosono M, Tatsuta T, Nitta K (2009) Binding of Silurus Asotus lectin to Gb3 on Raji cells causes disappearance of membrane-bound form of HSP70. Biochim Biophys Acta 1790:101–109PubMedCrossRefGoogle Scholar
  59. 59.
    Arispe N, Doh M, Simakova O, Kurganov B, De Maio A (2004) Hsc70 and Hsp70 interact with phosphatidylserine on the surface of PC12 cells resulting in a decrease of viability. FASEB J 18:1636–1645PubMedCrossRefGoogle Scholar
  60. 60.
    Schilling D, Gehrmann M, Steinem C, De Maio A, Pockley AG, Abend M, Molls M, Multhoff G (2009) Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells. FASEB J 23:2467–2477PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Nylandsted J, Gyrd-Hansen M, Danielewicz A, Fehrenbacher N, Lademann U, Hoyer-Hansen M, Weber E, Multhoff G, Rohde M, Jaattela M (2004) Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med 200:425–435PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Pockley AG, Shepherd J, Corton JM (1998) Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol Investig 27:367–377CrossRefGoogle Scholar
  63. 63.
    Zhu J, Quyyumi AA, Wu H, Csako G, Rott D, Zalles-Ganley A, Ogunmakinwa J, Halcox J, Epstein SE (2003) Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease. Arterioscler Thromb Vasc Biol 23:1055–1059PubMedCrossRefGoogle Scholar
  64. 64.
    Zhang X, He M, Cheng L, Chen Y, Zhou L, Zeng H, Pockley AG, Hu FB, Wu T (2008) Elevated heat shock protein 60 levels are associated with higher risk of coronary heart disease in Chinese. Circulation 118:2687–2693PubMedCrossRefGoogle Scholar
  65. 65.
    Zhang X, Xu Z, Zhou L, Chen Y, He M, Cheng L, Hu FB, Tanguay RM, Wu T (2010) Plasma levels of Hsp70 and anti-Hsp70 antibody predict risk of acute coronary syndrome. Cell Stress Chaperones 15:675–686PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Pockley AG, Wu R, Lemne C, Kiessling R, de Faire U, Frostegard J (2000) Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension 36:303–307PubMedCrossRefGoogle Scholar
  67. 67.
    Lewthwaite J, Owen N, Coates A, Henderson B, Steptoe A (2002) Circulating human heat shock protein 60 in the plasma of British civil servants: relationship to physiological and psychosocial stress. Circulation 106:196–201PubMedCrossRefGoogle Scholar
  68. 68.
    Krishnamurthy K, Kanagasabai R, Druhan LJ, Ilangovan G (2012) Heat shock protein 25-enriched plasma transfusion preconditions the heart against doxorubicin-induced dilated cardiomyopathy in mice. J Pharmacol Exp Ther 341:829–839PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Gehrmann M, Cervello M, Montalto G, Cappello F, Gulino A, Knape C, Specht HM, Multhoff G (2014) Heat shock protein 70 serum levels differ significantly in patients with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Front Immunol 5:307PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Liao WC, Wu MS, Wang HP, Tien YW, Lin JT (2009) Serum heat shock protein 27 is increased in chronic pancreatitis and pancreatic carcinoma. Pancreas 38:422–426PubMedCrossRefGoogle Scholar
  71. 71.
    Melle C, Ernst G, Escher N, Hartmann D, Schimmel B, Bleul A, Thieme H, Kaufmann R, Felix K, Friess HM, Settmacher U, Hommann M, Richter KK, Daffner W, Taubig H, Manger T, Claussen U, von Eggeling F (2007) Protein profiling of microdissected pancreas carcinoma and identification of HSP27 as a potential serum marker. Clin Chem 53:629–635PubMedCrossRefGoogle Scholar
  72. 72.
    Yuan J, Dunn P, Martinus RD (2011) Detection of Hsp60 in saliva and serum from type 2 diabetic and non-diabetic control subjects. Cell Stress Chaperones 16:689–693PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Oglesbee MJ, Herdman AV, Passmore GG, Hoffman WH (2005) Diabetic ketoacidosis increases extracellular levels of the major inducible 70-kDa heat shock protein. Clin Biochem 38:900–904PubMedCrossRefGoogle Scholar
  74. 74.
    Genth-Zotz S, Bolger AP, Kalra PR, von Haehling S, Doehner W, Coats AJ, Volk HD, Anker SD (2004) Heat shock protein 70 in patients with chronic heart failure: relation to disease severity and survival. Int J Cardiol 96:397–401PubMedCrossRefGoogle Scholar
  75. 75.
    Dybdahl B, Slordahl SA, Waage A, Kierulf P, Espevik T, Sundan A (2005) Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart 91:299–304PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Azuma K, Shichijo S, Takedatsu H, Komatsu N, Sawamizu H, Itoh K (2003) Heat shock cognate protein 70 encodes antigenic epitopes recognised by HLA-B4601-restricted cytotoxic T lymphocytes from cancer patients. Br J Cancer 89:1079–1085PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Faure O, Graff-Dubois S, Bretaudeau L, Derre L, Gross DA, Alves PM, Cornet S, Duffour MT, Chouaib S, Miconnet I, Gregoire M, Jotereau F, Lemonnier FA, Abastado JP, Kosmatopoulos K (2004) Inducible Hsp70 as target of anticancer immunotherapy: identification of HLA-A*0201-restricted epitopes. Int J Cancer 108:863–870PubMedCrossRefGoogle Scholar
  78. 78.
    Wu FH, Yuan Y, Li D, Liao SJ, Yan B, Wei JJ, Zhou YH, Zhu JH, Zhang GM, Feng ZH (2012) Extracellular HSPA1A promotes the growth of hepatocarcinoma by augmenting tumor cell proliferation and apoptosis-resistance. Cancer Lett 317:157–164PubMedCrossRefGoogle Scholar
  79. 79.
    Hunter-Lavin C, Davies EL, Bacelar MM, Marshall MJ, Andrew SM, Williams JH (2004) Hsp70 release from peripheral blood mononuclear cells. Biochem Biophys Res Commun 324:511–517PubMedCrossRefGoogle Scholar
  80. 80.
    Pittet JF, Lee H, Morabito D, Howard MB, Welch WJ, Mackersie RC (2002) Serum levels of Hsp 72 measured early after trauma correlate with survival. J Trauma 52:611–617. discussion 617PubMedGoogle Scholar
  81. 81.
    Ziegler TR, Ogden LG, Singleton KD, Luo M, Fernandez-Estivariz C, Griffith DP, Galloway JR, Wischmeyer PE (2005) Parenteral glutamine increases serum heat shock protein 70 in critically ill patients. Intensive Care Med 31:1079–1086PubMedCrossRefGoogle Scholar
  82. 82.
    Ganter MT, Ware LB, Howard M, Roux J, Gartland B, Matthay MA, Fleshner M, Pittet JF (2006) Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury. Am J Physiol Lung Cell Mol Physiol 291:L354–L361PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Flohe SB, Bangen JM, Flohe S, Agrawal H, Bergmann K, Schade FU (2007) Origin of immunomodulation after soft tissue trauma: potential involvement of extracellular heat-shock proteins. Shock 27:494–502PubMedCrossRefGoogle Scholar
  84. 84.
    Hecker JG, McGarvey M (2011) Heat shock proteins as biomarkers for the rapid detection of brain and spinal cord ischemia: a review and comparison to other methods of detection in thoracic aneurysm repair. Cell Stress Chaperones 16:119–131PubMedCrossRefGoogle Scholar
  85. 85.
    De Maio A, Vazquez D (2013) Extracellular heat shock proteins: a new location, a new function. Shock 40:239–246PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Njemini R, Lambert M, Demanet C, Mets T (2003) Elevated serum heat-shock protein 70 levels in patients with acute infection: use of an optimized enzyme-linked immunosorbent assay. Scand J Immunol 58:664–669PubMedCrossRefGoogle Scholar
  87. 87.
    Osorio-Caballero M, Perdigon-Palacio C, Garcia-Lopez G, Flores-Herrera O, Olvera-Sanchez S, Morales-Mendez I, Sosa-Gonzalez I, Acevedo JF, Guzman-Grenfell AM, Molina-Hernandez A, Diaz NF, Flores-Herrera H (2015) Escherichia coli-induced temporal and differential secretion of heat-shock protein 70 and interleukin-1beta by human fetal membranes in a two-compartment culture system. Placenta 36:262–269PubMedCrossRefGoogle Scholar
  88. 88.
    Molvarec A, Prohaszka Z, Nagy B, Szalay J, Fust G, Karadi I, Rigo J Jr (2006) Association of elevated serum heat-shock protein 70 concentration with transient hypertension of pregnancy, preeclampsia and superimposed preeclampsia: a case-control study. J Hum Hypertens 20:780–786PubMedCrossRefGoogle Scholar
  89. 89.
    Molvarec A, Tamasi L, Losonczy G, Madach K, Prohaszka Z, Rigo J Jr (2010) Circulating heat shock protein 70 (HSPA1A) in normal and pathological pregnancies. Cell Stress Chaperones 15:237–247PubMedCrossRefGoogle Scholar
  90. 90.
    Asea A, Jean-Pierre C, Kaur P, Rao P, Linhares IM, Skupski D, Witkin SS (2008) Heat shock protein-containing exosomes in mid-trimester amniotic fluids. J Reprod Immunol 79:12–17PubMedCrossRefGoogle Scholar
  91. 91.
    Walsh RC, Koukoulas I, Garnham A, Moseley PL, Hargreaves M, Febbraio MA (2001) Exercise increases serum Hsp72 in humans. Cell Stress Chaperones 6:386–393PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Febbraio MA, Ott P, Nielsen HB, Steensberg A, Keller C, Krustrup P, Secher NH, Pedersen BK (2002) Exercise induces hepatosplanchnic release of heat shock protein 72 in humans. J Physiol 544:957–962PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Periard JD, Ruell P, Caillaud C, Thompson MW (2012) Plasma Hsp72 (HSPA1A) and Hsp27 (HSPB1) expression under heat stress: influence of exercise intensity. Cell Stress Chaperones 17:375–383PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Santos TM, Sinzato YK, Gallego FQ, Iessi IL, Volpato GT, Dallaqua B, Damasceno DC (2015) Extracellular HSP70 levels in diabetic environment in rats. Cell Stress Chaperones 20:595–603PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Tsai TN, Lee TY, Liu MS, Chuang IC, Lu MC, Dong HP, Lue SI, Yang RC (2015) Release of endogenous heat shock protein 72 on the survival of sepsis in rats. J Surg Res 198:165–174PubMedCrossRefGoogle Scholar
  96. 96.
    Wilhelmus MM, Boelens WC, Otte-Holler I, Kamps B, de Waal RM, Verbeek MM (2006) Small heat shock proteins inhibit amyloid-beta protein aggregation and cerebrovascular amyloid-beta protein toxicity. Brain Res 1089:67–78PubMedCrossRefGoogle Scholar
  97. 97.
    Wilhelmus MM, Boelens WC, Otte-Holler I, Kamps B, Kusters B, Maat-Schieman ML, de Waal RM, Verbeek MM (2006) Small heat shock protein HspB8: its distribution in Alzheimer's disease brains and its inhibition of amyloid-beta protein aggregation and cerebrovascular amyloid-beta toxicity. Acta Neuropathol 111:139–149PubMedCrossRefGoogle Scholar
  98. 98.
    Evans CG, Wisen S, Gestwicki JE (2006) Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1-42) aggregation in vitro. J Biol Chem 281:33182–33191PubMedCrossRefGoogle Scholar
  99. 99.
    Carnini A, Scott LO, Ahrendt E, Proft J, Winkfein RJ, Kim SW, Colicos MA, Braun JE (2012) Cell line specific modulation of extracellular abeta42 by Hsp40. PLoS One 7:e37755PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Luo X, Tao L, Lin P, Mo X, Chen H (2012) Extracellular heat shock protein 72 protects schwann cells from hydrogen peroxide-induced apoptosis. J Neurosci Res 90:1261–1269PubMedCrossRefGoogle Scholar
  101. 101.
    Guzhova I, Kislyakova K, Moskaliova O, Fridlanskaya I, Tytell M, Cheetham M, Margulis B (2001) In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance. Brain Res 914:66–73PubMedCrossRefGoogle Scholar
  102. 102.
    Zhu Z, Li R, Stricker R, Reiser G (2015) Extracellular alpha-crystallin protects astrocytes from cell death through activation of MAPK, PI3K/Akt signaling pathway and blockade of ROS release from mitochondria. Brain Res 1620:17–28PubMedCrossRefGoogle Scholar
  103. 103.
    Nickel W, Seedorf M (2008) Unconventional mechanisms of protein transport to the cell surface of eukaryotic cells. Annu Rev Cell Dev Biol 24:287–308PubMedCrossRefGoogle Scholar
  104. 104.
    Wimley WC, Hristova K, Ladokhin AS, Silvestro L, Axelsen PH, White SH (1998) Folding of beta-sheet membrane proteins: a hydrophobic hexapeptide model. J Mol Biol 277:1091–1110PubMedCrossRefGoogle Scholar
  105. 105.
    Arispe N, De Maio A (2000) ATP and ADP modulate a cation channel formed by Hsc70 in acidic phospholipid membranes. J Biol Chem 275:30839–30843PubMedCrossRefGoogle Scholar
  106. 106.
    Macazo FC, White RJ (2014) Monitoring charge flux to quantify unusual ligand-induced ion channel activity for use in biological nanopore-based sensors. Anal Chem 86:5519–5525PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Armijo G, Okerblom J, Cauvi DM, Lopez V, Schlamadinger DE, Kim J, Arispe N, De Maio A (2014) Interaction of heat shock protein 70 with membranes depends on the lipid environment. Cell Stress Chaperones 19:877–886PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    McCallister C, Kdeiss B, Nikolaidis N (2016) Biochemical characterization of the interaction between HspA1A and phospholipids. Cell Stress Chaperones 21:41–53PubMedCrossRefGoogle Scholar
  109. 109.
    Lopez V, Cauvi DM, Arispe N, De Maio A (2016) Bacterial Hsp70 (DnaK) and mammalian Hsp70 interact differently with lipid membranes. Cell Stress Chaperones 21:609–616PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Multhoff G, Hightower LE (1996) Cell surface expression of heat shock proteins and the immune response. Cell Stress Chaperones 1:167–176PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Multhoff G (2007) Heat shock protein 70 (Hsp70): membrane location, export and immunological relevance. Methods 43:229–237PubMedCrossRefGoogle Scholar
  112. 112.
    Mambula SS, Calderwood SK (2006) Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol 177:7849–7857PubMedCrossRefGoogle Scholar
  113. 113.
    Andrei C, Dazzi C, Lotti L, Torrisi MR, Chimini G, Rubartelli A (1999) The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles. Mol Biol Cell 10:1463–1475PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Evdonin AL, Martynova MG, Bystrova OA, Guzhova IV, Margulis BA, Medvedeva ND (2006) The release of Hsp70 from A431 carcinoma cells is mediated by secretory-like granules. Eur J Cell Biol 85:443–455PubMedCrossRefGoogle Scholar
  115. 115.
    Janas T, Janas MM, Sapon K, Janas T (2015) Mechanisms of RNA loading into exosomes. FEBS Lett 589:1391–1398PubMedCrossRefGoogle Scholar
  116. 116.
    Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, Boireau W, Rouleau A, Simon B, Lanneau D, De Thonel A, Multhoff G, Hamman A, Martin F, Chauffert B, Solary E, Zitvogel L, Garrido C, Ryffel B, Borg C, Apetoh L, Rebe C, Ghiringhelli F (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471PubMedPubMedCentralGoogle Scholar
  117. 117.
    Li W, Sahu D, Tsen F (2012) Secreted heat shock protein-90 (Hsp90) in wound healing and cancer. Biochim Biophys Acta 1823:730–741PubMedCrossRefGoogle Scholar
  118. 118.
    Gupta S, Knowlton AA (2007) HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. Am J Physiol Heart Circ Physiol 292:H3052–H3056PubMedCrossRefGoogle Scholar
  119. 119.
    Merendino AM, Bucchieri F, Campanella C, Marciano V, Ribbene A, David S, Zummo G, Burgio G, Corona DF, Conway de Macario E, Macario AJ, Cappello F (2010) Hsp60 is actively secreted by human tumor cells. PLoS One 5:e9247PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Evdokimovskaya Y, Skarga Y, Vrublevskaya V, Morenkov O (2010) Secretion of the heat shock proteins HSP70 and HSC70 by baby hamster kidney (BHK-21) cells. Cell Biol Int 34:985–990PubMedCrossRefGoogle Scholar
  121. 121.
    Broquet AH, Thomas G, Masliah J, Trugnan G, Bachelet M (2003) Expression of the molecular chaperone Hsp70 in detergent-resistant microdomains correlates with its membrane delivery and release. J Biol Chem 278:21601–21606PubMedCrossRefGoogle Scholar
  122. 122.
    Chen S, Bawa D, Besshoh S, Gurd JW, Brown IR (2005) Association of heat shock proteins and neuronal membrane components with lipid rafts from the rat brain. J Neurosci Res 81:522–529PubMedCrossRefGoogle Scholar
  123. 123.
    Thery C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1999) Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 147:599–610PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Chaput N, Flament C, Viaud S, Taieb J, Roux S, Spatz A, Andre F, LePecq JB, Boussac M, Garin J, Amigorena S, Thery C, Zitvogel L (2006) Dendritic cell derived-exosomes: biology and clinical implementations. J Leukoc Biol 80:471–478PubMedCrossRefGoogle Scholar
  125. 125.
    Lancaster GI, Febbraio MA (2005) Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem 280:23349–23355PubMedCrossRefGoogle Scholar
  126. 126.
    Clayton A, Turkes A, Navabi H, Mason MD, Tabi Z (2005) Induction of heat shock proteins in B-cell exosomes. J Cell Sci 118:3631–3638PubMedCrossRefGoogle Scholar
  127. 127.
    Mathew A, Bell A, Johnstone RM (1995) Hsp-70 is closely associated with the transferrin receptor in exosomes from maturing reticulocytes. Biochem J 308(Pt 3):823–830PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Conde-Vancells J, Rodriguez-Suarez E, Embade N, Gil D, Matthiesen R, Valle M, Elortza F, Lu SC, Mato JM, Falcon-Perez JM (2008) Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes. J Proteome Res 7:5157–5166PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    McCready J, Sims JD, Chan D, Jay DG (2010) Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation. BMC Cancer 10:294PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Hegmans JP, Bard MP, Hemmes A, Luider TM, Kleijmeer MJ, Prins JB, Zitvogel L, Burgers SA, Hoogsteden HC, Lambrecht BN (2004) Proteomic analysis of exosomes secreted by human mesothelioma cells. Am J Pathol 164:1807–1815PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Anand PK, Anand E, Bleck CK, Anes E, Griffiths G (2010) Exosomal Hsp70 induces a pro-inflammatory response to foreign particles including mycobacteria. PLoS One 5:e10136PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Maecker HT, Todd SC, Levy S (1997) The tetraspanin superfamily: molecular facilitators. FASEB J 11:428–442PubMedCrossRefGoogle Scholar
  133. 133.
    Bhatnagar S, Shinagawa K, Castellino FJ, Schorey JS (2007) Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood 110:3234–3244PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    O'Neill HC, Quah BJ (2008) Exosomes secreted by bacterially infected macrophages are proinflammatory. Sci Signal 1:pe8PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Surgery, School of MedicineUniversity of California San DiegoLa JollaUSA
  2. 2.Department of Neuroscience, School of MedicineUniversity of California San DiegoLa JollaUSA
  3. 3.Center for Investigations of Health and Education DisparitiesUniversity of California San DiegoLa JollaUSA

Personalised recommendations