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Inflammatory mediators in diabetic and non-diabetic lumbosacral radiculoplexus neuropathy

Acta Neuropathologica volume 115, pages 231–239 (2008)Cite this article

Abstract

Nerve microvasculitis and ischemic injury appear to be the primary and important pathogenic alterations in lumbosacral radiculoplexus neuropathy of patients with (DLRPN) and without (LRPN) diabetes mellitus (DM). Here, we examine the involvement of inflammatory mediators in DLRPN and LRPN. Paraffin sections of sural nerves from 19 patients with DLRPN, 13 patients with LRPN, and 20 disease control patients were immunostained for intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor κB (NF-κB). The findings were correlated with histopathology. The pathologic and immunohistochemical alterations of DLRPN and LRPN nerves were indistinguishable. The nerves of both types of LRPN had a significantly greater number of ICAM-1 positive vessels than did the controls (P < 0.01). TNF-α expression was seen in Schwann cells and some macrophages of DLRPN and LRPN nerves, whereas IL-6 expression was minimal. There was greater NF-κB immunoreactivity in vessels and endoneurial cells of DLRPN and LRPN nerves than of the controls (P < 0.001). NF-κB expression correlated with the number of empty nerve strands (P < 0.01) and the frequency of axonal degeneration (P < 0.05), whereas TNF-α expression correlated inversely with the number of empty nerve strands of teased fibers (P < 0.05). Our findings suggest that up-regulation of inflammatory mediators target different cells at different disease stages and that these mediators may be sequentially involved in an immune-mediated inflammatory process that is shared by both DLRPN and LRPN. Up-regulated inflammatory mediators may be immunotherapeutic targets in these two conditions.

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References

  1. Andorfer B, Kieseier BC, Mathey E, Armati P, Pollard J, Oka N, Hartung HP (2001) Expression and distribution of transcription factor NF-kappaB and inhibitor IkappaB in the inflamed peripheral nervous system. J Neuroimmunol 116:226–232

    PubMed  Article  CAS  Google Scholar 

  2. Asbury AK (1977) Proximal diabetic neuropathy. Ann Neurol 2:179–180

    PubMed  Article  CAS  Google Scholar 

  3. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M (1995) Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis (see comment). Science 270:286–290

    PubMed  Article  CAS  Google Scholar 

  4. Bastron JA, Thomas JE (1981) Diabetic polyradiculopathy: clinical and electromyographic findings in 105 patients. Mayo ClinProc 56:725–732

    CAS  Google Scholar 

  5. Bonetti B, Valdo P, Stegagno C, Tanel R, Zanusso GL, Ramarli D, Fiorini E, Turazzi S, Carner M, Moretto G (2000) Tumor necrosis factor alpha and human Schwann cells: signalling and phenotype modulation without cell death. J Neuropathol Exp Neurol 59(1):74–84

    PubMed  CAS  Google Scholar 

  6. Chokroverty S, Reyes MG, Rubino FA (1977) Bruns-Garland syndrome of diabetic amyotrophy. Trans Am Neurol Assoc 102:173–177

    PubMed  CAS  Google Scholar 

  7. Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T (1995) Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 9:899–909

    PubMed  CAS  Google Scholar 

  8. Deprez M, Lubke U, Verlaet M, Debrus S, Delvenne P, Martin JJ (2001) Detection of cytokines in human sural nerve biopsies: an immunohistochemical and molecular study. Acta Neuropathol (Berl) 101(4):393–404

    CAS  Google Scholar 

  9. Dyck PJ, Dyck PJB, Engelstad J (2005) Pathologic alterations of nerves. In: Dyck PJ, Thomas PK (eds Peripheral neuropathy, 4th edn. Elsevier, Philadelphia, pp 733–830

    Google Scholar 

  10. Dyck PJB, Dyck PJ (1999) Diabetic polyneuropathy. In: Dyck PJ, Thomas PK (eds) Diabetic neuropathy. W. B. Saunders, Philadelphia, pp 255–278

    Google Scholar 

  11. Dyck PJB, Engelstad J, Norell J, Dyck PJ (2000) Microvasculitis in non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN): similarity to the diabetic variety (DLSRPN). J Neuropath Exp Neurol 59:525–538

    PubMed  CAS  Google Scholar 

  12. Dyck PJB, Norell JE, Dyck PJ (1999) Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 53:2113–2121

    PubMed  CAS  Google Scholar 

  13. Dyck PJB, Norell JE, Dyck PJ (2001) Non-diabetic lumbosacral radiculoplexus neuropathy. Natural history, outcome and comparison with the diabetic variety. Brain 124:1197–1207

    PubMed  Article  CAS  Google Scholar 

  14. Empl M, Renaud S, Erne B, Fuhr P, Straube A, Schaeren-Wiemers N, Steck AJ (2001) TNF-alpha expression in painful and nonpainful neuropathies. Neurology 56(10):1371–1377

    PubMed  CAS  Google Scholar 

  15. Evans BA, Stevens JC, Dyck PJ (1981) Lumbosacral plexus neuropathy. Neurology 31:1327–1330

    PubMed  CAS  Google Scholar 

  16. Garland H (1955) Diabetic amyotrophy. Br Med J 2:1287–1296

    PubMed  CAS  Google Scholar 

  17. Hall SM, Redford EJ, Smith KJ (2000) Tumour necrosis factor-alpha has few morphological effects within the dorsal columns of the spinal cord, in contrast to its effects in the peripheral nervous system. J Neuroimmunol 106(1–2):130–136

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  19. Kawamura N, Schmeichel AM, Wang Y, Schmelzer JD, Low PA (2006) Multiple effects of hypothermia on inflammatory response following ischemia-reperfusion injury in experimental ischemic neuropathy. Exp Neurol 202(2):487–496

    PubMed  Article  CAS  Google Scholar 

  20. Kelkar PM, Masood M, Parry GJ (2000) Distinctive pathologic findings in proximal diabetic neuropathy (diabetic amyotrophy). Neurology 55(1):83–88

    PubMed  CAS  Google Scholar 

  21. Lawrence T, Bebien M, Liu GY, Nizet V, Karin M (2005) IKKalpha limits macrophage NF-kappa B activation and contributes to the resolution of inflammation. Nature 434:1138–1143

    PubMed  Article  CAS  Google Scholar 

  22. Lindenlaub T, Sommer C (2003) Cytokines in sural nerve biopsies from inflammatory and non-inflammatory neuropathies. Acta Neuropathol (Berl) 105(6):593–602

    CAS  Google Scholar 

  23. Llewelyn JG, Thomas PK, King RHM (1998) Epineurial microvasculitis in proximal diabetic neuropathy. J Neurol 245(3):159–165

    PubMed  Article  CAS  Google Scholar 

  24. Mazzeo A, Aguennouz M, Messina C, Vita G (2004) Immunolocalization and activation of transcription factor nuclear factor kappa B in dysimmune neuropathies and familial amyloidotic polyneuropathy. Arch Neurol 61(7):1097–1102

    PubMed  Article  Google Scholar 

  25. Mitsui Y, Okamoto K, Martin DP, Schmelzer JD, Low PA (1999) The expression of proinflammatory cytokine mRNA in the sciatic-tibial nerve of ischemia-reperfusion injury. Brain Res 844(1–2):192–195

    PubMed  Article  CAS  Google Scholar 

  26. Nukada H, Lynch CD, McMorran PD (2002) Aggravated reperfusion injury in STZ-diabetic nerve. J Peripher Nerv Syst 7:37–43

    PubMed  Article  Google Scholar 

  27. Nukada H, McMorran PD, Shimizu J (2000) Acute inflammatory demyelination in reperfusion nerve injury. Ann Neurol 47(1):71–79

    PubMed  Article  CAS  Google Scholar 

  28. Oka N, Akiguchi I, Kawasaki T, Mizutani K, Satoi H, Kimura J (1998) Tumor necrosis factor-alpha in peripheral nerve lesions. Acta Neuropathol (Berl) 95(1):57–62

    Article  CAS  Google Scholar 

  29. Oppenhheim JJ, Feldman M (2001) Introduction to the role of cytokines in innate and defense and adaptive immunity. In: Oppenhheim JJ, Feldman M (eds) Cytokine reference. Academic, New York, pp 3–20

    Google Scholar 

  30. Pascoe MK, Low PA, Windebank AJ, Litchy WJ (1997) Subacute diabetic proximal neuropathy. Mayo Clin Proc 72(12):1123–1132

    PubMed  CAS  Article  Google Scholar 

  31. Redford EJ, Hall SM, Smith KJ (1995) Vascular changes and demyelination induced by the intraneural injection of tumour necrosis factor. Brain 118(Pt 4):869–878

    PubMed  Article  Google Scholar 

  32. Said G, Lacroix C, Lozeron P, Ropert A, Plante V, Adams D (2003) Inflammatory vasculopathy in multifocal diabetic neuropathy. Brain 126:376–385

    PubMed  Article  Google Scholar 

  33. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr (1995) Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 270:283–286

    PubMed  Article  CAS  Google Scholar 

  34. Siebert H, Bruck W (2003) The role of cytokines and adhesion molecules in axon degeneration after peripheral nerve axotomy: a study in different knockout mice. Brain Res 960(1–2):152–156

    PubMed  Article  CAS  Google Scholar 

  35. Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory diseases. J Clin Invest 107(1):7–11

    PubMed  CAS  Google Scholar 

  36. Vougioukas VI, Roeske S, Michel U, Bruck W (1998) Wallerian degeneration in ICAM-1-deficient mice. Am J Pathol 152:241–249

    PubMed  CAS  Google Scholar 

  37. Wang Y, Schmeichel AM, Iida H, Schmelzer JD, Low PA (2006) Enhanced inflammatory response via activation of NF-kappaB in acute experimental diabetic neuropathy subjected to ischemia-reperfusion injury. J Neurol Sci 247:47–52

    PubMed  Article  CAS  Google Scholar 

  38. Weinhold B, Ruther U (1997) Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene. Biochem J 327(Pt 2):425–429

    PubMed  CAS  Google Scholar 

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Author notes

  1. Nobutoshi Kawamura

    Present address: Department of Neurology, Kyushu University, Fukuoka, 812-8582, Japan

Affiliations

  1. Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Nobutoshi Kawamura, P. James B. Dyck, Ann M. Schmeichel, JaNean K. Engelstad, Phillip A. Low & Peter J. Dyck

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  1. Nobutoshi Kawamura
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  2. P. James B. Dyck
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  3. Ann M. Schmeichel
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  4. JaNean K. Engelstad
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  5. Phillip A. Low
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  6. Peter J. Dyck
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Corresponding author

Correspondence to P. James B. Dyck.

Additional information

Nobutoshi Kawamura was a Research Fellow in Phillip A. Low’s Peripheral Neuropathy Research Laboratory.

Supported in part by grants obtained from the National Institute of Neurological Disease and Stroke (NS 36797) (NS 32352) (NS 22352) (NS 43364).

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Kawamura, N., Dyck, P.J.B., Schmeichel, A.M. et al. Inflammatory mediators in diabetic and non-diabetic lumbosacral radiculoplexus neuropathy. Acta Neuropathol 115, 231–239 (2008). https://doi.org/10.1007/s00401-007-0326-2

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  • DOI: https://doi.org/10.1007/s00401-007-0326-2

Keywords

  • Diabetic amyotrophy
  • Diabetic lumbosacral radiculoplexus neuropathy
  • Intercellular adhesion molecule-1
  • Nuclear factor kappa B
  • Tumor necrosis factor
  • Peripheral neuropathy