ErbB2 receptor tyrosine kinase signaling mediates early demyelination induced by leprosy bacilli.
Demyelination is a common pathologic feature in many neurodegenerative diseases including infection with leprosy-causing Mycobacterium leprae. 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 demyelination 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 phosphorylation. 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 antibody, 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.
Tapinos
Nikos
N
The Rockefeller University, Bronk Building, Room 501, Box 172, 1230 York Avenue, New York, New York 10021, USA.
Ohnishi
Makoto
M
Rambukkana
Anura
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D002070:Butadienes / Q000494:pharmacology; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007918:Leprosy / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009166:Mycobacterium leprae / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012583:Schwann Cells / Q000201:enzymology / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism / Q000382:microbiology / Q000648:ultrastructure; D015398:Signal Transduction; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002070:Butadienes; D004791:Enzyme Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009570:Nitriles; D011743:Pyrimidines; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C113580:U 0126; C410026:PKI 166