Advertisement

Hsp60 in Inflammatory Disorders

  • Antonella Marino Gammazza
  • Giovanni Tomasello
  • Angelo Leone
  • Abdo Jurjus
Chapter
Part of the Heat Shock Proteins book series (HESP, volume 18)

Abstract

Heat shock proteins (HSP) including HSP60 are immunogenic proteins shared by particular microbial agents and mammals. HSP60 has been implicated in multiple inflammatory disorders and autoimmune diseases mostly through its interactions with the immune system. Such diseases include inflammatory bowel disease, chronic obstructive pulmonary disease, Hashimoto’s thyroiditis, myasthenia gravis, multiple sclerosis and even atherosclerosis plaques among others. It is present in the cytosol, cell membrane, cell surface as well as in the extracellular space and in the circulation. As a super antigen, HSP60 has the dual role as an immunomodulator and as a biomarker, a node molecule in balance between health and disease. Deciphering the mechanisms of HSP60 interactions with the immune system could lead to the development of new therapeutic strategies.

Keywords

Autoimmunity Homeostasis HSP60 Immune system Immunoregulation Inflammatory disorders 

Abbreviations

AChR

Muscle acetylcholine receptor

APC

Antigen-presenting cells

CD

Crohn’s disease

COPD

Chronic obstructive pulmonary disease

CR

Chemokine receptor

CREB

cAMP response element-binding protein

CSF

Cerebral spinal fluid

ERK

Extracellular signal–regulated kinases

HSP

Heat shock proteins

HSP60

Heat shock protein 60

HT

Hashimoto’s thyroiditis

IBD

Inflammatory bowel disease

IFNɣ

Interferon gamma

IL

Interleukin

LPS

Lipopolysaccharides

MG

Myasthenia gravis

MHC

Major histocompatibility complex

MS

Multiple sclerosis

NFkB

Nuclear factor kappa-light-chain-enhancer of activated B cells

PBMC

Peripheral blood mononuclear cells

PKB

Protein kinase B

TG

Thyroglobulin

TLR

Innate toll-like receptor

TPO

Thyroid peroxidase

Tregs

T regulatory cells

UC

Ulcerative colitis

Notes

Acknowledgements

Part of this work was funded by the Italian National Operational Programme (PON) «Imprese e Competitività» 2014-2020 FESR, grant awarded by the Italian Ministry of Economic Development to the project titled «Gestione di un servizio integrato multicentrico di diagnostica e terapia personalizzata in oncologia» (Project code: F/090012/01-02/X36).

References

  1. Ahmed R, Al-Shaikh S, Akhtar M (2000) Hashimoto thyroiditis: a century later. Adv Anat Pathol 19:181–186CrossRefGoogle Scholar
  2. Astarloa R, Martinez Castrillo JC (1996) Humoral response to the human heat shock 60 kDa protein in myasthenia gravis. J Neurol Sci 135:182–183PubMedCrossRefPubMedCentralGoogle Scholar
  3. Baca-Estrada ME, Gupta RS, Stead RH et al (1994) Intestinal expression and cellular immune responses to human heat-shock protein 60 in Crohn’s disease. Dig Dis Sci 39:498–506PubMedCrossRefPubMedCentralGoogle Scholar
  4. Barone R, Rappa F, Macaluso F et al (2016) Alcoholic liver disease: a mouse model reveals protection by Lactobacillus fermentum. Clin Transl Gastroenterol 7:e138PubMedPubMedCentralCrossRefGoogle Scholar
  5. Baumgart DC, Carding SR (2007) Inflammatory bowel disease: cause and immunobiology. Lancet 369:1627–1640PubMedCrossRefPubMedCentralGoogle Scholar
  6. Bellavia M, Tomasello G, Romeo M et al (2013) Gut microbiota imbalance and chaperoning system malfunction are central to ulcerative colitis pathogenesis and can be counteracted with specifically designed probiotics: a working hypothesis. Med Microbiol Immunol 202:393–406PubMedCrossRefPubMedCentralGoogle Scholar
  7. Bendz H, Ruhland SC, Pandya MJ et al (2007) Human heat shock protein 70 enhances tumor antigen presentation through complex formation and intracellular antigen delivery without innate immune signaling. J Biol Chem 282:31688–31702PubMedCrossRefPubMedCentralGoogle Scholar
  8. Bene L, Fust G, Huszti Z et al (2002) Impaired humoral immune response against mycobacterial 65-kDa heat shock protein (HSP65) in patients with inflammatory bowel disease. Dig Dis Sci 47:1432–1437PubMedCrossRefPubMedCentralGoogle Scholar
  9. Bohen SP, Kralli A, Yamamoto KR (1995) Hold ‘em and fold ‘em: chaperones and signal transduction. Science 268:1303–1304PubMedCrossRefPubMedCentralGoogle Scholar
  10. Borges JC, Ramos CH (2005) Protein folding assisted by chaperones. Protein Pept Lett 12:257–261PubMedCrossRefPubMedCentralGoogle Scholar
  11. Campanella C, Bucchieri F, Merendino AM et al (2012) The odyssey of Hsp60 from tumor cells to other destinations includes plasma membrane-associated stages and Golgi and exosomal protein-trafficking modalities. PLoS One 7:e42008PubMedPubMedCentralCrossRefGoogle Scholar
  12. Campanella C, Caruso Bavisotto C, Marino Gammazza A et al (2014) Exosomal heat shock proteins as a new players in tumor cell-to-cell communication. J Circ Biomark 3:10CrossRefGoogle Scholar
  13. Campanella C, D’Anneo A, Marino Gammazza A et al (2016) The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells. Oncotarget 7:28849–28867CrossRefGoogle Scholar
  14. Cappello F, Di Stefano A, David S et al (2006) Hsp60 and Hsp10 down-regulation predicts bronchial epithelial carcinogenesis in smokers with chronic obstructive pulmonary disease. Cancer 107:2417–2424CrossRefGoogle Scholar
  15. Cappello F, Marino Gammazza A, Zummo L et al (2010) Hsp60 and AChR cross-reactivity in myasthenia gravis: an update. J Neurol Sci 292:117–118PubMedCrossRefPubMedCentralGoogle Scholar
  16. Cappello F, Caramori G, Campanella C et al (2011) Convergent sets of data from in vivo and in vitro methods point to an active role of Hsp60 in chronic obstructive pulmonary disease pathogenesis. PLoS One 6:e28200PubMedPubMedCentralCrossRefGoogle Scholar
  17. Coelho V, Faria AM (2012) HSP60: issues and insights on its therapeutic use as an immunoregulatory agent. Front Immunol 12:97Google Scholar
  18. Cohen IR (2007) Real and artificial immune systems: computing thestate of the body. Nat Rev Immunol 7:569–574Google Scholar
  19. Cohen-Sfady M, Nussbaum G, Pevsner-Fischer M, Mor F, Carmi P, Zanin-Zhorov A, Lider O, Cohen IR (2005) Heat shock protein 60 activates B cells via the TLR4-MyD88 pathway. J Immunol 175:3594–3602PubMedCrossRefPubMedCentralGoogle Scholar
  20. Czarnecka AM, Campanella C, Zummo G et al (2006) Mitochondrial chaperones in cancer: from molecular biology to clinical diagnostics. Cancer Biol Ther 5:714–720CrossRefGoogle Scholar
  21. Davies EL, Bacelar MM, Marshall MJ et al (2006) Heat shock proteins form part of a danger signal cascade in response to lipopolysaccharide and GroEL. Clin Exp Immunol 145:183–189PubMedPubMedCentralCrossRefGoogle Scholar
  22. Decramer M, Janssens W, Miravitlles M (2012) Chronic obstructive pulmonary disease. Lancet 379:1341–1351PubMedCrossRefPubMedCentralGoogle Scholar
  23. Di Stefano A, Caramori G, Gnemmi I et al (2009) Association of increased CCL5 and CXCL7 chemokine expression with neutrophil activation in severe stable COPD. Thorax 64:968–975PubMedCrossRefPubMedCentralGoogle Scholar
  24. Efthymiou G, Dardiotis E, Liaskos C et al (2016) Anti-hsp60 antibody responses based on helicobacter pylori in patients with multiple sclerosis: (ir)relevance to disease pathogenesis. J Neuroimmunol 298:19–23CrossRefGoogle Scholar
  25. Gamble E, Grootendorst DC, Hattotuwa K et al (2007) Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis. Eur Respir J 30:467–471PubMedCrossRefPubMedCentralGoogle Scholar
  26. Gandhi R, Kumar D, Burns EJ et al (2010) Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells. Nat Immunol 11:846–853PubMedPubMedCentralCrossRefGoogle Scholar
  27. Ghosh JC, Siegelin MD, Dohi T et al (2010) Heat shock protein 60 regulation of the mitochondrial permeability transition pore in tumor cells. Cancer Res 70:8988–8993PubMedPubMedCentralCrossRefGoogle Scholar
  28. Greening DW, Gopal SK, Xu R et al (2015) Exosomes and their roles in immune regulation and cancer. Semin Cell Dev Biol 40:72–81PubMedCrossRefPubMedCentralGoogle Scholar
  29. Henderson B, Pockley AG (2010) Molecular chaperones and protein-folding catalysts as intercellular signaling regulators in immunity and inflammation. J Leukoc Biol 88:445–462CrossRefGoogle Scholar
  30. Henderson B, Calderwood SK, Coates AR et al (2010) Caught with their PAMPs down? The extracellular signaling actions of molecular chaperones are not due to microbial contaminants. Cell Stress Chaperones 15:123–141PubMedCrossRefPubMedCentralGoogle Scholar
  31. Huszti Z, Bene L, Kovacs A et al (2004) Low levels of antibodies against E. coli and mycobacterial 65kDa heat shock proteins in patients with inflammatory bowel disease. Inflamm Res 53:551–555PubMedCrossRefPubMedCentralGoogle Scholar
  32. Kunisawa J, Shastri N (2006) Hsp90alpha chaperones large C-terminally extended proteolytic intermediates in the MHC class I antigen processing pathway. Immunity 24:523–534PubMedCrossRefPubMedCentralGoogle Scholar
  33. Lorini R, Gastaldi R, Traggiai C et al (2003) Hashimoto’s thyroiditis. Pediatr Endocrinol Rev 1:205–211PubMedPubMedCentralGoogle Scholar
  34. Marino Gammazza A, Bucchieri F, Grimaldi LM et al (2012) The molecular anatomy of human Hsp60 and its similarity with that of bacterial orthologs and acetylcholine receptor reveal a potential pathogenetic role of anti-chaperonin immunity in myasthenia gravis. Cell Mol Neurobiol 32:943–947CrossRefGoogle Scholar
  35. Marino Gammazza A, Rizzo M, Citarrella R et al (2014) Elevated blood Hsp60, its structural similarities and cross-reactivity with thyroid molecules, and its presence on the plasma membrane of oncocytes point to the chaperonin as an immunopathogenic factor in Hashimoto’s thyroiditis. Cell Stress Chaperones 19:343–353CrossRefGoogle Scholar
  36. Marino Gammazza A, Caruso Bavisotto C, David S (2017) HSP60 is a ubiquitous player in the physiological and pathogenic interactions between the chaperoning and the immune systems. Curr Immunol Rev 13:44–55Google Scholar
  37. Marino GA, Caruso Bavisotto C, Barone R, de Macario EC, Macario AJ (2016) Alzheimer’s disease and molecular chaperones: current knowledge and the future of chaperonotherapy. CurrPharm Des 22:4040–4049Google Scholar
  38. Nussbaum G, Zanin-Zhorov A, Quintana F, Lider O, Cohen IR (2006 Oct) Peptide p277 of HSP60 signals T cells: inhibition of inflammatory chemotaxis. Int Immunol 18(10):1413–1419PubMedCrossRefPubMedCentralGoogle Scholar
  39. Osterloh A, Veit A, Gessner A, Fleischer B, Breloer M (2008) Hsp60-mediated T cell stimulation is independent of TLR4 and IL-12. Int Immunol 20:433–443PubMedCrossRefPubMedCentralGoogle Scholar
  40. Peetermans WE, D’Haens GR, Ceuppens JL et al (1995) Mucosal expression by B7-positive cells of the 60-kilodalton heat-shock protein in inflammatory bowel disease. Gastroenterology 108:75–82PubMedCrossRefPubMedCentralGoogle Scholar
  41. Pei W, Tanaka K, Huang SC et al (2016) Extracellular HSP60 triggers tissue regeneration and wound healing by regulating inflammation and cell proliferation. NPJ Regen Med 1:16013PubMedPubMedCentralCrossRefGoogle Scholar
  42. Pockley AG, Muthana M, Calderwood SK (2008) The dual immunoregulatory roles of stress proteins. Trends Biochem Sci 33:71–79CrossRefGoogle Scholar
  43. Pratt WB (1997) The role of the hsp90-based chaperone system in signal transduction by nuclear receptors and receptors signaling via MAP kinase. Annu Rev Pharmacol Toxicol 37:297–326PubMedCrossRefPubMedCentralGoogle Scholar
  44. Puga Yung GL, Fidler M, Albani E et al (2009) Heat shock protein-derived T-cell epitopes contribute to autoimmune inflammation in pediatric Crohn’s disease. PLoS One 4:e7714PubMedPubMedCentralCrossRefGoogle Scholar
  45. Quintana FJ, Cohen IR (2011) The HSP60 immune system network. Trends Immunol 32:89–95CrossRefGoogle Scholar
  46. Quintana FJ, Basso AS, Iglesias AH et al (2008) Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 23:23Google Scholar
  47. Quintana FJ, Farez MF, Izquierdo G, Lucas M, Cohen IR, Weiner HL (2012) Antigen microarrays identify CNS-produced autoantibodies in RRMS. Neurology 78:532–539PubMedPubMedCentralCrossRefGoogle Scholar
  48. Rappa F, Farina F, Zummo G et al (2012) HSP-molecular chaperones in cancer biogenesis and tumor therapy: an overview. Anticancer Res 32:5139–5150Google Scholar
  49. Rodolico V, Tomasello G, Zerilli M et al (2010) Hsp60 and Hsp10 increase in colon mucosa of Crohn’s disease and ulcerative colitis. Cell Stress Chaperones 15:877–884PubMedPubMedCentralCrossRefGoogle Scholar
  50. Ruiz-Vazquez E, de Castro P (2003) “2-6-11” motif in heat shock protein 60 and central nervous system antigens: a preliminary study in multiple sclerosis patients. J Physiol Biochem 59:1–9PubMedCrossRefPubMedCentralGoogle Scholar
  51. Rupp J, Droemann D, Goldmann T et al (2004) Alveolar epithelial cells type II are major target cells for C. pneumoniae in chronic but not in acute respiratory infection. FEMS Immunol Med Microbiol 41:197–203PubMedCrossRefPubMedCentralGoogle Scholar
  52. Sangiorgi C, Vallese D, Gnemmi I et al (2017) HSP60 activity on human bronchial epithelial cells. Int J Immunopathol Pharmacol 30:333–340PubMedPubMedCentralCrossRefGoogle Scholar
  53. Stevens TR, Winrow VR, Blake DR et al (1992) Circulating antibodies to heat-shock protein 60 in Crohn’s disease and ulcerative colitis. Clin Exp Immunol 90:271–274PubMedPubMedCentralCrossRefGoogle Scholar
  54. Sukegawa Y, Kamiya S, Yagita A et al (2000) Induction of autoimmune colitis by Yersinia enterocolitica 60-kilodalton heat-shock protein. Scand J Gastroenterol 35:1188–1193PubMedCrossRefPubMedCentralGoogle Scholar
  55. Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593PubMedCrossRefGoogle Scholar
  56. Tomasello G, Rodolico V, Zerilli M et al (2011) Changes in immunohistochemical levels and subcellular localization after therapy and correlation and colocalization with CD68 suggest a pathogenetic role of Hsp60 in ulcerative colitis. Appl Immunohistochem Mol Morphol 19:552–561CrossRefGoogle Scholar
  57. Tonello L, Conway de Macario E, Marino Gammazza A et al (2015) Data mining-based statistical analysis of biological data uncovers hidden significance: clustering Hashimoto’s thyroiditis patients based on the response of their PBMC with IL-2 and IFN-gamma secretion to stimulation with Hsp60. Cell Stress Chaperones 20:391–395PubMedCrossRefPubMedCentralGoogle Scholar
  58. Tsan MF, Gao B (2009) Heat shock proteins and immune system. J Leukoc Biol 85:905–910CrossRefGoogle Scholar
  59. Tsuji N, Fukuda K, Nagata Y, Okada H, Haga A, Hatakeyama S, Yoshida S, Okamoto T, Hosaka M, Sekine K, Ohtaka K, Yamamoto S, Otaka M, Grave E, Itoh H (2014) The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90. FEBS Open Bio 4:796–803PubMedPubMedCentralCrossRefGoogle Scholar
  60. Ulmansky R, Landstein D, Moallem E et al (2015) A humanized monoclonal antibody against heat shock protein 60 suppresses murine arthritis and colitis and skews the cytokine balance toward an anti-inflammatory response. J Immunol 194:5103–5109PubMedCrossRefPubMedCentralGoogle Scholar
  61. Van Eden W, van der Zee R, Prakken B (2005) Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol 5:318–330CrossRefGoogle Scholar
  62. Vanderpump MP, Tunbridge WM (2002) Epidemiology and prevention of clinical and subclinical hypothyroidism. Thyroid 12:839–347PubMedCrossRefPubMedCentralGoogle Scholar
  63. Yagita A, Sukegawa Y, Maruyama S et al (1999) Mouse colitis induced by Escherichia coli producing Yersinia enterocolitica 60-kilodalton heat-shock protein: light and electron microscope study. Dig Dis Sci 44:445–451PubMedCrossRefPubMedCentralGoogle Scholar
  64. Zanin-Zhorov A, Tal G, Shivtiel S, Cohen M, Lapidot T, Nussbaum G, Margalit R, Cohen IR, Lider O (2005) Heat shock protein 60 activates cytokine-associated negative regulator suppressor of cytokine signaling 3 in T cells: effects on signaling, chemotaxis, and inflammation. J Immunol 175:276–285CrossRefGoogle Scholar
  65. Zanin-Zhorov A, Cahalon L, Tal G, Margalit R, Lider O (2006 Jul) Cohen IR. Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling. J Clin Invest 116(7):2022–2032. Epub 2006 Jun 8. Retraction in: J Clin Invest. 2018 Jun 1;128(6):2651Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Antonella Marino Gammazza
    • 1
    • 2
  • Giovanni Tomasello
    • 1
  • Angelo Leone
    • 1
  • Abdo Jurjus
    • 3
    • 4
  1. 1.Department of Biomedicine, Neuroscience and Advanced DiagnosticsUniversity of PalermoPalermoItaly
  2. 2.Euro-Mediterranean Institute of Science and TechnologyPalermoItaly
  3. 3.Department of Anatomy, Cell Biology and Physiological SciencesAmerican University of BeirutBeirutLebanon
  4. 4.Department of Anatomy and Regenerative BiologyGeorge Washington UniversityWashington, DCUSA

Personalised recommendations