*Receptor tyrosine kinases play a significant role in human
oligodendrocyte inflammation and cell death associated with the Lyme
disease bacterium /Borrelia burgdorferi/.
Parthasarathy G, Philipp MT.
Journal of Neuroinflammation. 2017 May 30;14(1):110.
Abstract In previous studies, human oligodendrocytes were demonstrated to undergo
apoptosis in the presence of /Borrelia burgdorferi/ under an
inflammatory milieu. Subsequently, we determined that the MEK/ERK
pathway played a significant role in triggering downstream inflammation
as well as apoptosis. However, the identity of receptors triggered by
exposure to /B. burgdorferi/ and initiating signaling events was unknown.
*Methods*
In this study, we explored the role of several TLR and EGFR/FGFR/PDGFR
tyrosine kinase pathways in inducing inflammation in the presence of /B.
burgdorferi/, using siRNA and/or inhibitors, in MO3.13 human
oligodendrocytes. Cell death and apoptosis assays were also carried out
in the presence or absence of specific receptor inhibitors along with
the bacteria to determine the role of these receptors in apoptosis
induction. The expression pattern of specific receptors with or without
/B. burgdorferi/ was also determined.
*Results*
TLRs 2 and 5 had a minimal role in inducing inflammation, particularly
IL-6 production. Rather, their effect was mostly inhibitory, with TLR2
downregulation significantly upregulating CXCL8, and CXCL (1,2,3)
levels, and TLR5 likely having a similar role in CXCL8, CXCL(1,2,3), and
CCL5 levels. TLR4 contributed mostly towards CCL5 production. On the
other hand, inhibition of all three EGF/FGF/PDGF receptors significantly
downregulated all five of the inflammatory mediators tested even in the
presence of /B. burgdorferi/. Their inhibition also downregulated
overall cell death and apoptosis levels. The expression pattern of these
receptors, as assessed by immunohistochemistry indicated that the PDGFRβ
receptor was the most predominantly expressed receptor, followed by
FGFR, although no significant differences were discernible between
presence and absence of bacteria. Interestingly, inhibition of
individual EGFR, FGFR, or PDGFR receptors did not indicate an individual
role for any of these receptors in the overall downregulation of
pathogenesis. Contrarily, suppression of FGFR signaling alone in the
presence of bacteria significantly upregulated inflammatory mediator
levels indicating that it might control an inhibitory pathway when
triggered individually.
*Conclusions*
Unlike TLRs, EGF/FGF/PDGF receptors collectively play a significant role
in the inflammation and apoptosis of human oligodendrocytes as mediated
by /B. burgdorferi/. It is likely that these three receptors need to be
triggered simultaneously to achieve this effect.
link to article