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

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.

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.

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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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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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