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The MEK/ERK pathway is the primary conduit for Borrelia burgdorferi-induced inflammation and P53-mediated apoptosis in oligodendrocytes

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Abstract

Lyme neuroborreliosis (LNB) affects both the central and peripheral nervous systems. In a rhesus macaque model of LNB we had previously shown that brains of rhesus macaques inoculated with Borrelia burgdorferi release inflammatory mediators, and undergo oligodendrocyte and neuronal cell death. In vitro analysis of this phenomenon indicated that while B. burgdorferi can induce inflammation and apoptosis of oligodendrocytes per se, microglia are required for neuronal apoptosis. We hypothesized that the inflammatory milieu elicited by the bacterium in microglia or oligodendrocytes contributes to the apoptosis of neurons and glial cells, respectively, and that downstream signaling events in NFkB and/or MAPK pathways play a role in these phenotypes. To test these hypotheses in oligodendrocytes, several pathway inhibitors were used to determine their effect on inflammation and apoptosis, as induced by B. burgdorferi. In a human oligodendrocyte cell line (MO3.13), inhibition of the ERK pathway in the presence of B. burgdorferi markedly reduced inflammation, followed by the JNK, p38 and NFkB pathway inhibition. In addition to eliciting inflammation, B. burgdorferi also increased total p53 protein levels, and suppression of the ERK pathway mitigated this effect. While inhibition of p53 had a minimal effect in reducing inflammation, suppression of the ERK pathway or p53 reduced apoptosis as measured by active caspase-3 activity and the TUNEL assay. A similar result was seen in primary human oligodendrocytes wherein suppression of ERK or p53 reduced apoptosis. It is possible that inflammation and apoptosis in oligodendrocytes are divergent arms of MAPK pathways, particularly the MEK/ERK pathway.

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Acknowledgments

This study was supported by the National Institute of Neurologic Disorders and Stroke through Grant NS048952, and by the National Center for Research Resources/Office of Research Infrastructure Programs of the National Institutes of Health through Grant P51RR000164/P51OD011104. We thank the TNPRC Pathogen Detection and Quantification Core Laboratory for help with the multiplex ELISA assays. Ms. Robin Rodriguez of the TNPRC Media Laboratory is gratefully acknowledged for her assistance with graphics.

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The authors declare that they have no conflict of interest.

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  1. Division of Bacteriology and Parasitology, Tulane National Primate Research Center, 18703, Three Rivers Road, Covington, LA, 70433, USA

    Geetha Parthasarathy & Mario T. Philipp

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  1. Geetha Parthasarathy
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Correspondence to Mario T. Philipp.

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Parthasarathy, G., Philipp, M.T. The MEK/ERK pathway is the primary conduit for Borrelia burgdorferi-induced inflammation and P53-mediated apoptosis in oligodendrocytes. Apoptosis 19, 76–89 (2014). https://doi.org/10.1007/s10495-013-0913-8

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