Skip to main content

Advertisement

SpringerLink
Log in

The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy

  • Regular Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Oxidative stress and nuclear factor-κB (NF-κB) activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases. Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand Nε-carboxymethyllysine (CML) results in the activation of NF-κB and the production of proinflammatory cytokines. To determine whether engagement of RAGE contributes to the pathogenesis of inflammatory myopathies, we performed immunohistochemical studies on the presence of CML-modified proteins, RAGE and activated NF-κB in muscle biopsies of patients with polymyositis (PM, n=10), dermatomyositis (DM, n=10), limb girdle muscular dystrophy (LGMD, n=10) and in 10 controls with normal muscle biopsy results. In inflammatory myopathies CML, RAGE and NF-κB were detected in mononuclear cells and in regenerating muscle fibers. CML, NF-κB and, to a lesser extent, RAGE were also found in degenerating muscle fibers, but colocalization of CML, RAGE and NF-κB was only seen in infiltrating mononuclear cells and regenerating muscle fibers. Immunofluorescence double labeling demonstrated an expression of CML, RAGE and NF-κB in CD4-, CD8-, CD22- and CD68-positive mononuclear cells. Western blot analysis showed an increased immunoreactivity for CML-modified proteins in PM and DM. In LGMD, CML, RAGE and NF-κB were found in regenerating muscle fibers and less frequently in degenerating muscle fibers, and with lower staining intensities than in inflammatory myopathies. Our data suggests that the CML-RAGE-NF-κB pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM. RAGE-mediated NF-κB activation may be involved in muscle fiber regeneration in inflammatory myopathies and LGMD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2 a–c
Fig. 3 a–d
Fig. 4

Similar content being viewed by others

References

  1. Ames PR, Alves J, Murat I, Isenberg DA, Nourooz-Zadeh J (1999) Oxidative stress in systemic lupus erythematosus and allied conditions with vascular involvement. Rheumatology (Oxford) 38:529–534

    Google Scholar 

  2. Arahata K, Engel AG (1984) Monoclonal antibody analysis of mononuclear cells in myopathies. I. Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol 16:193–208

    CAS  PubMed  Google Scholar 

  3. Baeuerle PA, Henkel T (1994) Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12:141–179

    CAS  PubMed  Google Scholar 

  4. Baghdiguian S, Richard I, Martin M, Coopman P, Beckmann JS, Mangeat P, Lefranc G (2001) Pathophysiology of limb girdle muscular dystrophy type 2A: hypothesis and new insights into the IkappaBalpha/NF-kappaB survival pathway in skeletal muscle. J Mol Med 79:254–261

    Google Scholar 

  5. Bierhaus A, Nawroth PP (2003) Modulation of the vascular endothelium during infection—the role of NF-kappa B activation. Contrib Microbiol 10:86–105

    CAS  PubMed  Google Scholar 

  6. Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T, Luther T, Berentshtein E, Tritschler H, Muller M et al. (1997) Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 46:1481–1490

    CAS  PubMed  Google Scholar 

  7. Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Kloting I et al. (2001) Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes 50:2792–2808

    CAS  PubMed  Google Scholar 

  8. Bierhaus A, Haslbeck KM, Humpert PM, Liliensiek B, Dehmer T, Morcos M, Sayed AA, Andrassy M, Schiekofer S, Schneider JG et al. (2004) Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J Clin Invest 114:1741–1751

    Article  CAS  PubMed  Google Scholar 

  9. Brownlee M, Cerami A, Vlassara H (1988) Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318:1315–1321

    CAS  PubMed  Google Scholar 

  10. Cameron NE, Cotter MA, Archibald V, Dines KC, Maxfield EK (1994) Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats. Diabetologia 37:449–459

    Article  CAS  PubMed  Google Scholar 

  11. Collins T, Cybulsky MI (2001) NF-kappaB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest 107:255–264

    CAS  PubMed  Google Scholar 

  12. Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KA, Stein H, Mason DY (1984) Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem 32:219–229

    CAS  PubMed  Google Scholar 

  13. De Bleecker JL, Meire VI, Declercq W, Van Aken EH (1999) Immunolocalization of tumor necrosis factor-alpha and its receptors in inflammatory myopathies. Neuromuscul Disord 9:239–246

    Article  PubMed  Google Scholar 

  14. Engel AG, Arahata K (1984) Monoclonal antibody analysis of mononuclear cells in myopathies. II. Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol 16:209–215

    Google Scholar 

  15. Gempel KE, Wagner EM, Schleicher ED (1994) Production and characterization of antibodies against carboxymethyllysine-modified proteins. In: Maillard reactions in chemistry, food and health. The royal society of Chemistry, Cambridge

  16. Haslbeck KM, Schleicher ED, Friess U, Kirchner A, Neundorfer B, Heuss D (2002) N(epsilon)-Carboxymethyllysine in diabetic and non-diabetic polyneuropathies. Acta Neuropathol 104:45–52

    Article  CAS  PubMed  Google Scholar 

  17. Haslbeck KM, Bierhaus A, Schleicher E, Kirchner A, Nawroth P, Schlotzer U, Neundorfer B, Heuss D (2004) Receptor for advanced glycation endproduct (RAGE)-mediated nuclear factor-kappaB activation in vasculitic neuropathy. Muscle Nerve 29:853–860

    Article  CAS  PubMed  Google Scholar 

  18. Hein G, Franke S (2002) Are advanced glycation end-product-modified proteins of pathogenetic importance in fibromyalgia? Rheumatology (Oxford) 41:1163–1167

    Google Scholar 

  19. Hunter RB, Stevenson E, Koncarevic A, Mitchell-Felton H, Essig DA, Kandarian SC (2002) Activation of an alternative NF-kappaB pathway in skeletal muscle during disuse atrophy. FASEB J 16:529–538

    Article  CAS  PubMed  Google Scholar 

  20. Karin M, Delhase M (2000) The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling. Semin Immunol 12:85–98

    Article  CAS  PubMed  Google Scholar 

  21. Karpati G, Carpenter S (1993) Pathology of the inflammatory myopathies. Baillieres Clin Neurol 2:527–556

    CAS  PubMed  Google Scholar 

  22. Kasper M, Roehlecke C, Witt M, Fehrenbach H, Hofer A, Miyata T, Weigert C, Funk RH, Schleicher ED (2000) Induction of apoptosis by glyoxal in human embryonic lung epithelial cell line L132. Am J Respir Cell Mol Biol 23:485–491

    CAS  PubMed  Google Scholar 

  23. Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM (1999) N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 274:31740–31749

    Google Scholar 

  24. Liptay S, Bachem M, Hacker G, Adler G, Debatin KM, Schmid RM (1999) Inhibition of nuclear factor kappa B and induction of apoptosis in T-lymphocytes by sulfasalazine. Br J Pharmacol 128:1361–1369

    Article  CAS  PubMed  Google Scholar 

  25. Monici MC, Aguennouz M, Mazzeo A, Messina C, Vita G (2003) Activation of nuclear factor-kappaB in inflammatory myopathies and Duchenne muscular dystrophy. Neurology 60:993–997

    CAS  PubMed  Google Scholar 

  26. Quehenberger P, Bierhaus A, Fasching P, Muellner C, Klevesath M, Hong M, Stier G, Sattler M, Schleicher E, Speiser W, Nawroth PP (2000) Endothelin 1 transcription is controlled by nuclear factor-kappaB in AGE-stimulated cultured endothelial cells. Diabetes 49:1561–1570

    CAS  PubMed  Google Scholar 

  27. Schleicher ED, Wagner E, Nerlich AG (1997) Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 99:457–468

    CAS  PubMed  Google Scholar 

  28. Schmidt AM, Hori O, Chen JX, Li JF, Crandall J, Zhang J, Cao R, Yan SD, Brett J, Stern D (1995) Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest 96:1395–1403

    CAS  PubMed  Google Scholar 

  29. Schmidt AM, Yan SD, Yan SF, Stern DM (2001) The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest 108:949–955

    Article  CAS  PubMed  Google Scholar 

  30. Sorci G, Riuzzi F, Agneletti AL, Marchetti C, Donato R (2003) S100B inhibits myogenic differentiation and myotube formation in a RAGE-independent manner. Mol Cell Biol 23:4870–4881

    Google Scholar 

  31. Sorci G, Riuzzi F, Agneletti AL, Marchetti C, Donato R (2004) S100B causes apoptosis in a myoblast cell line in a RAGE-independent manner. J Cell Physiol 199:274–283

    Google Scholar 

  32. Sorci G, Riuzzi F, Arcuri C, Giambanco I, Donato R (2004) Amphoterin stimulates myogenesis and counteracts the antimyogenic factors basic fibroblast growth factor and S100B via RAGE binding. Mol Cell Biol 24:4880–4894

    Google Scholar 

  33. Stangel M, Mix E, Zettl UK, Gold R (2001) Oxides and apoptosis in inflammatory myopathies. Microsc Res Tech 55:249–258

    Article  CAS  PubMed  Google Scholar 

  34. Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory diseases. J Clin Invest 107:7–11

    CAS  PubMed  Google Scholar 

  35. Tews DS, Goebel HH (1996) Cytokine expression profile in idiopathic inflammatory myopathies. J Neuropathol Exp Neurol 55:342–347

    Google Scholar 

  36. Tews DS, Goebel HH (1998) Cell death and oxidative damage in inflammatory myopathies. Clin Immunol Immunopathol 87:240–247

    Google Scholar 

  37. Thiele K, Bierhaus A, Autschbach F, Hofmann M, Stremmel W, Thiele H, Ziegler R, Nawroth PP (1999) Cell specific effects of glucocorticoid treatment on the NF-kappaBp65/IkappaBalpha system in patients with Crohn’s disease. Gut 45:693–704

    CAS  PubMed  Google Scholar 

  38. Van der Kooi AJ, Barth PG, Busch HF, Haan R de, Ginjaar HB, Essen AJ van, Hooff LJ van, Howeler CJ, Jennekens FG, Jongen P et al. (1996) The clinical spectrum of limb girdle muscular dystrophy. A survey in The Netherlands. Brain 119:1471–1480

    PubMed  Google Scholar 

  39. Van der Kooi AJ, Ginjaar HB, Busch HF, Wokke JH, Barth PG, Visser M de (1998) Limb girdle muscular dystrophy: a pathological and immunohistochemical reevaluation. Muscle Nerve 21:584–590

    Article  PubMed  Google Scholar 

  40. Wautier JL, Zoukourian C, Chappey O, Wautier MP, Guillausseau PJ, Cao R, Hori O, Stern D, Schmidt AM (1996) Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest 97:238–243

    CAS  PubMed  Google Scholar 

  41. Yan SD, Roher A, Chaney M, Zlokovic B, Schmidt AM, Stern D (2000) Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid beta-peptide. Biochim Biophys Acta 1502:145–157

    CAS  PubMed  Google Scholar 

  42. Yan SS, Wu ZY, Zhang HP, Furtado G, Chen X, Yan SF, Schmidt AM, Brown C, Stern A, LaFaille J et al. (2003) Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system. Nat Med 9:287–293

    Article  CAS  PubMed  Google Scholar 

  43. Yang CC, Askanas V, Engel WK, Alvarez RB (1998) Immunolocalization of transcription factor NF-kappaB in inclusion-body myositis muscle and at normal human neuromuscular junctions. Neurosci Lett 254:77–80

    Article  CAS  PubMed  Google Scholar 

  44. Yeh CH, Sturgis L, Haidacher J, Zhang XN, Sherwood SJ, Bjercke RJ, Juhasz O, Crow MT, Tilton RG, Denner L (2001) Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. Diabetes 50:1495–1504

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank E. Ganzmann, U. Schellmann, B. Zieher and H. Fischer for their skilful technical assistance. This work was in part supported by grants of the IZKF Erlangen-Nürnberg (D.H.), the deutsche Forschungsgemeinschaft (SFB 405 to P.P.N.), the European foundation for he study of diabetes (A.B.), and juvenile diabetes research foundation (A.B.; P.P.N.).

Conflict of interest:

No information supplied

Author information

Authors and Affiliations

  1. Department of Neurology, University Erlangen-Nürnberg, Schwabachanlage 6, 91054, Erlangen, Germany

    K. M. Haslbeck, A. Kirchner, E. Pauli, B. Neundörfer & D. Heuss

  2. Department of Medicine IV, University Tübingen, Tübingen, Germany

    U. Friess & E. D. Schleicher

  3. Department of Medicine I, University Heidelberg, Heidelberg, Germany

    A. Bierhaus & P. P. Nawroth

Authors
  1. K. M. Haslbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. U. Friess
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. D. Schleicher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Bierhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. P. Nawroth
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Kirchner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Pauli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B. Neundörfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D. Heuss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. M. Haslbeck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haslbeck, K.M., Friess, U., Schleicher, E.D. et al. The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy. Acta Neuropathol 110, 247–254 (2005). https://doi.org/10.1007/s00401-005-1043-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-005-1043-3

Keywords

Search

Navigation