Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli

Abstract

Activation of extracellular signal-regulated kinase (Erk) 1͞2, which plays a critical role in diverse cellular processes, including cell proliferation, is known to be mediated by the canonical Rafmitogen-activated protein kinase kinase (MEK) kinase cascade. Alternative MEK-independent signaling pathways for Erk1͞2 activation in mammalian cells are not known. During our studies of human primary Schwann cell response to long-term infection of Mycobacterium leprae, the causative organism of leprosy, we identified that intracellular M. leprae activated Erk1͞2 directly by lymphoid cell kinase (p56Lck), a Src family member, by means of a PKC-dependent and MEK-independent signaling pathway. Activation of this signaling induced nuclear accumulation of cyclin D1, G 1͞S-phase progression, and continuous proliferation, but without transformation. Thus, our data reveal a previously unknown signaling mechanism of glial cell proliferation, which might play a role in dedifferentiation as well as nerve regeneration and degeneration. Our findings may also provide a potential mechanism by which an obligate intracellular bacterial pathogen like M. leprae subverts nervous system signaling to propagate its cellular niche for colonization and long-term bacterial survival.cell signaling ͉ cell cycle ͉ peripheral nerve ͉ human ͉ Mycobacterium leprae

Expression of CD1d Molecules by Human Schwann Cells and Potential Interactions with Immunoregulatory Invariant NK T Cells

“…To confirm the findings from experiments using CD1d ϩ transformed human Schwann cell lines, we conducted similar experiments using previously characterized human primary Schwann cells, which had been isolated from human adult peripheral nerve tissue and expanded up to 3-4 passages (22). Using fluorescence microscopy, we confirmed that IFN-␥-treated primary Schwann cells expressed CD1d in a diffuse and mostly homogenous distribution similar to that observed for MHC class I molecules (Fig.…”

“…Isolation, purification, and characterization of primary Schwann cells were previously described (21,22).…”

Morphological and functional characterizations of Schwann cells stimulated with Mycobacterium leprae

“…Recent data have shown that, in order to adhere and activate SC, M. leprae and its glycolipid component PGL-I utilize molecules on the basal lamina and membrane of SC (e.g., laminin α2 and the neuregulin receptor Erb2, respectively). These events result in demyelination in rat SC co-cultures (Vincent et al 2000, Tapinos & Rambukkana 2005.…”

Mycobacterium leprae downregulates the expression of PHEX in Schwann cells and osteoblasts

“…Increasing efforts over the past decade to understand important early events in the interaction of M. leprae with peripheral nerves have resulted in the characterization of bacterial adhesins and receptors involved in M. leprae attachment to Schwann cells (de Melo Marques et al 2000, Rambukkana 2004, Soares de Lima et al 2005. The effects of M. leprae on myelin sheath integrity (Rambukkana et al 2002, Tapinos et al 2006) and on Schwann cell proliferation (Tapinos & Rambukkana 2005) have been investigated as well.…”