J Neuroinflammation. 2017 May 30;14(1):110. doi: 10.1186/s12974-017-0883-9.
Receptor tyrosine kinases play a significant role in human oligodendrocyte inflammation and cell death associated with the Lyme disease bacterium Borrelia burgdorferi.
Parthasarathy G1, Philipp MT2.
1 Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, 18703, Three Rivers Road, Covington, LA, 70433, USA.
2 Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, 18703, Three Rivers Road, Covington, LA, 70433, USA.
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.
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.
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.
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.
B. burgdorferi; Human oligodendrocytes; Inflammation; Lyme neuroborreliosis; Receptor tyrosine kinases
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From the free, full text link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450372/
Lyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi, is a morbid form of Lyme disease with complex neurological sequelae. LNB manifests in about 15% of patients with primary erythema migrans, and may be evidenced as a lymphocytic meningo-radiculitis, lymphocytic meningitis, cranial neuritis, radiculoneuritis, radiculoneuropathy, and/or, rarely, encephalitis and myelitis . The pathogenesis of LNB is not clearly understood. We have established a rhesus macaque model and several in vitro and ex vivo models to help delineate mechanisms of acute LNB. Intrathecal inoculation of live B. burgdorferi in rhesus macaques elicited in these animals signs of acute LNB, including leptomeningitis, radiculitis, inflammatory lesions in dorsal root ganglia (DRG), accompanied by glial and neuronal apoptosis in the DRG .
Unlike previous data, the overall immune response from human oligodendrocytes, upon exposure to B. burgdorferi, results from activation of primarily three receptor tyrosine kinases, with as yet unknown activation mechanisms. Such activation also contributes to cell death processes, further underscoring the observation that inflammation in the nervous system due to B. burgdorferi results in apoptosis of neuroglial cells. The key receptors that were identified in this study may lead to the uncovering of novel pathogenic mechanisms in LNB.