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ErbB2 receptor tyrosine kinase signaling mediates early demyelination induced by leprosy bacilli

Nature Medicine volume 12, pages 961–966 (2006)Cite this article

A Corrigendum to this article was published on 01 September 2006

This article has been updated

Abstract

Demyelination is a common pathologic feature in many neurodegenerative diseases including infection with leprosy-causing Mycobacterium leprae1,2,3. Because of the long incubation time and highly complex disease pathogenesis, the management of nerve damage in leprosy, as in other demyelinating diseases, is extremely difficult. Therefore, an important challenge in therapeutic interventions is to identify the molecular events that occur in the early phase before the progression of the disease. Here we provide evidence that M. leprae–induced demyelination4,5 is a result of direct bacterial ligation to and activation of ErbB2 receptor tyrosine kinase (RTK) signaling without ErbB2-ErbB3 heterodimerization, a previously unknown mechanism that bypasses the neuregulin-ErbB3–mediated ErbB2 phosphorylation6,7,8,9. MEK-dependent Erk1 and Erk2 (hereafter referred to as Erk1/2) signaling is identified as a downstream target of M. leprae–induced ErbB2 activation that mediates demyelination. Herceptin (trastuzumab), a therapeutic humanized ErbB2-specific antibody9,10, inhibits M. leprae binding to and activation of ErbB2 and Erk1/2 in human primary Schwann cells, and the blockade of ErbB2 activity by the small molecule dual ErbB1-ErbB2 kinase inhibitor PKI-166 (ref. 11) effectively abrogates M. leprae–induced myelin damage in in vitro and in vivo models. These results may have implications for the design of ErbB2 RTK–based therapies for both leprosy nerve damage and other demyelinating neurodegenerative diseases.

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Figure 1: Demyelination induced by the attachment of M. leprae to Schwann cell–axon units is mediated by the activation of Erk1/2 through the MEK-dependent signaling pathway.
Figure 2: M. leprae activates ErbB2 receptor tyrosine kinase without ErbB3 heterodimerization: ErbB2 as an upstream receptor for mediating M. leprae–induced Erk1/2 activation.
Figure 3: ErbB2 is sufficient for M. leprae–cell interaction and the activation of Erk1/2: the relationship of M. leprae binding to ErbB2 with laminin-2 on myelinating Schwann cell–axon units.
Figure 4: The small-molecule ErbB2 kinase inhibitor PKI 166 blocks M. leprae–induced ErbB2 phosphorylation and demyelination in vitro and in vivo.

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Change history

  • 17 August 2006

    In the version of this article initially published, the middle panel of Figure 4d incorrectly reported the percentage of demyelination in M. leprae–treated cultures. The percentage should be 67 ± 3.1 instead of 7 ± 3.1. The error has been corrected in the HTML and PDF versions of the article.

Notes

  1. NOTE: In the version of this article initially published, the middle panel of Figure 4d incorrectly reported the percentage of demyelination in M. leprae-treated cultures. The percentage should be 67 ± 3.1 instead of 7 ± 3.1. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Stoner, G.L. Importance of the neural predilection of Mycobacterium leprae in leprosy. Lancet 2, 994–996 (1979).

    Article  CAS  Google Scholar 

  2. Job, C.K. Nerve damage in leprosy. Int. J. Lepr. Other Mycobact. Dis. 57, 532–539 (1989).

    CAS  PubMed  Google Scholar 

  3. Johnson, P.C. Peripheral nerve pathology. in Textbook of Neuropathology, 3rd edn. (eds Davis, R.L. & Robertson, D.M.) 1233–1323 (Baltimore, Lippincott William & Wilkins, 1997).

    Google Scholar 

  4. Rambukkana, A., Zanazzi, G., Tapinos, N. & Salzer, J.L. Contact-dependent demyelination by Mycobacterium leprae in the absence of immune cells. Science 296, 927–931 (2002).

    Article  CAS  Google Scholar 

  5. Rambukkana, A. Mycobacterium leprae-induced demyelination: a model for early nerve degeneration. Curr. Opin. Immunol. 16, 511–518 (2004).

    Article  CAS  Google Scholar 

  6. Garratt, A.N., Britsch, S. & Birchmeier, C. Neuregulin, a factor with many functions in the life of a schwann cell. Bioessays 22, 987–996 (2000).

    Article  CAS  Google Scholar 

  7. Chen, S. et al. Neuregulin 1-erbB signaling is necessary for normal myelination and sensory function. J. Neurosci. 26, 3079–3086 (2006).

    Article  CAS  Google Scholar 

  8. Michailov, G.V. et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700–703 (2004).

    Article  CAS  Google Scholar 

  9. Yarden, Y. & Sliwkowski, M.X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2, 127–137 (2001).

    Article  CAS  Google Scholar 

  10. Hynes, N.E. & Lane, H.A. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer 5, 341–354 (2005).

    Article  CAS  Google Scholar 

  11. Mellinghoff, I.K. et al. HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer Cell 6, 517–527 (2004).

    Article  CAS  Google Scholar 

  12. Tapinos, N. & Rambukkana, A. Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli. Proc. Natl. Acad. Sci. USA 102, 9188–9193 (2005).

    Article  CAS  Google Scholar 

  13. Zanazzi, G. et al. Glial growth factor/neuregulin inhibits Schwann cell myelination and induces demyelination. J. Cell Biol. 152, 1289–1299 (2001).

    Article  CAS  Google Scholar 

  14. Harrisingh, M.C. et al. The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation. EMBO J. 23, 3061–3071 (2004).

    Article  CAS  Google Scholar 

  15. Guertin, A.D., Zhang, D.P., Mak, K.S., Alberta, J.A. & Kim, H.A. Microanatomy of axon/glial signaling during Wallerian degeneration. J. Neurosci. 25, 3478–3487 (2005).

    Article  CAS  Google Scholar 

  16. Jessen, K.R. & Mirsky, R. The origin and development of glial cells in peripheral nerves. Nat. Rev. Neurosci. 6, 671–682 (2005).

    Article  CAS  Google Scholar 

  17. Rambukkana, A., Salzer, J.L., Yurchenco, P.D. & Tuomanen, E.I. Neural targeting of Mycobacterium leprae mediated by the G domain of the laminin-alpha2 chain. Cell 88, 811–821 (1997).

    Article  CAS  Google Scholar 

  18. Rambukkana, A. et al. Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae. Science 282, 2076–2079 (1998).

    Article  CAS  Google Scholar 

  19. Ng, V. et al. Role of the cell wall phenolic glycolipid-1 in the peripheral nerve predilection of Mycobacterium leprae. Cell 103, 511–524 (2000).

    Article  CAS  Google Scholar 

  20. Tsiper, M.V. & Yurchenco, P.D. Laminin assembles into separate basement membrane and fibrillar matrices in Schwann cells. J. Cell Sci. 115, 1005–1015 (2002).

    CAS  PubMed  Google Scholar 

  21. Davis, R.J. Transcriptional regulation by MAP kinases. Mol. Reprod. Dev. 42, 459–467 (1995).

    Article  CAS  Google Scholar 

  22. Cussac, D. et al. A SOS-derived peptidimer blocks the Ras signaling pathway by binding both Grb2 SH3 domains and displays antiproliferative activity. FASEB J. 13, 31–38 (1999).

    Article  CAS  Google Scholar 

  23. Nagy, P. et al. Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy. J. Cell Sci. 112, 1733–1741 (1999).

    CAS  PubMed  Google Scholar 

  24. Scott, G.K. et al. p185HER2 signal transduction in breast cancer cells. J. Biol. Chem. 266, 14300–14305 (1991).

    CAS  PubMed  Google Scholar 

  25. Pierce, J.H. et al. Signal transduction through the EGF receptor transfected in IL-3-dependent hematopoietic cells. Science 239, 628–631 (1988).

    Article  CAS  Google Scholar 

  26. Ling, B.C. et al. Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis. Cancer Cell 7, 65–75 (2005).

    Article  CAS  Google Scholar 

  27. Mendelsohn, J. The epidermal growth factor receptor as a target for cancer therapy. Endocr. Relat. Cancer 8, 3–9 (2001).

    Article  CAS  Google Scholar 

  28. Garratt, A.N., Voiculescu, O., Topilko, P., Charnay, P. & Birchmeier, C.A. Dual role of ErbB2 in myelination and in expansion of the Schwann cell precursor pool. J. Cell Biol. 148, 1035–1046 (2000).

    Article  CAS  Google Scholar 

  29. Fregien, N.L., White, L.A., Bunge, M.B. & Wood, P.M. Forskolin increases neuregulin receptors in human Schwann cells without increasing receptor mRNA. Glia 49, 24–35 (2005).

    Article  Google Scholar 

  30. Truman, R.W. & Krahenbuhl, J.L. Viable M. leprae as a research reagent. Int. J. Lepr. Other Mycobact. Dis. 69, 1–12 (2001).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank J. Krahenbuhl for providing viable, freshly harvested, nu/nu mouse–derived M. leprae, and P. Wood and the University of Miami Organ Procurement Organization for the provision of human peripheral nerve tissues from which human Schwann cells were derived. We also thank E.C. Gotschlich, V.A. Fischetti for continuing support and J.L. Salzer for initial support. Our thanks also extend to L. White and C. Eastby for assistance in isolation and preparation of Schwann cell cultures, H. Xu for animal experiments, W. Chow for initial identification of Erk1/2 phosphorylation and other technical assistance and H. Shio for electron microscopy. We acknowledge S. Puma for participating in this study through Rockefeller University Precollege Science Education Program. This work was supported by R01 grants from NIAID (A145816) and NINDS (NS45187) to A.R.

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Authors and Affiliations

  1. The Rockefeller University, Bronk Building, Room 501, Box 172, 1230 York Avenue, New York, 10021, New York, USA

    Nikos Tapinos, Makoto Ohnishi & Anura Rambukkana

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  1. Nikos Tapinos
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Correspondence to Anura Rambukkana.

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Supplementary information

Supplementary Fig. 1

Rat and human Schwann cells do not induce apoptosis after M. leprae treatment. (PDF 604 kb)

Supplementary Fig. 2

M. leprae directly bind to extracellular domain of ErbB2 receptor. (PDF 1780 kb)

Supplementary Fig. 3

Human primary Schwann cell proliferation induced by the cell attachment of M. leprae is inhibited by Herceptin antibody 4D5. (PDF 256 kb)

Supplementary Fig. 4

Relationship of M. leprae binding to ErbB2 with laminin-2 on myelinating Schwann cell–axon units. (PDF 1080 kb)

Supplementary Fig. 5

PKI-166 alone does not affect myelin sheath in vivo. (PDF 2504 kb)

Supplementary Methods (PDF 149 kb)

Supplementary Note (PDF 80 kb)

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Tapinos, N., Ohnishi, M. & Rambukkana, A. ErbB2 receptor tyrosine kinase signaling mediates early demyelination induced by leprosy bacilli. Nat Med 12, 961–966 (2006). https://doi.org/10.1038/nm1433

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