Brain inflammation plays a central role in multiple sclerosis (MS). Dimethylfumarate (DMF), the main ingredient of an oral formulation of fumaric acid esters with proven therapeutic efficacy in psoriasis, has recently been found to ameliorate the course of relapsing-remitting MS. Glial cells are the effector cells of neuroinflammation; however, little is known of the effect of DMF on microglia and astrocytes. The purpose of this study was to use an established in vitro model of brain inflammation to determine if DMF modulates the release of neurotoxic molecules from microglia and astrocytes, thus inhibiting glial inflammation. Methods: Primary microglial and astrocytic cell cultures were prepared from cerebral cortices of neonatal rats. The control cells were treated with LPS, an accepted inducer of pro-inflammatory properties in glial cells, and the experimental groups with LPS and DMF in different concentrations. After stimulation/incubation, the generation of nitric oxide (NO) in the cell culture supernatants was determined by measuring nitrite accumulation in the medium using Griess reagent. After 6 hours of treatment RT-PCR was used to determine transcription levels of iNOS, IL-1beta, IL-6 and TNF-alpha mRNA in microglial and astrocytic cell cultures initially treated with DMF, followed after 30 min by LPS treatment. Moreover, we investigated possible involvement of the ERK and Nrf-2 transduction pathway in microglia using western blot analysis.

Lyme disease, which is transmitted to humans through the bite of a tick,
is currently the most frequently reported vector-borne illness in the
northern hemisphere. Borrelia burgdorferi is the bacterium that causes
Lyme disease and it is known to readily induce inflammation within a
variety of infected tissues. Many of the neurological signs and symptoms
that may affect patients with Lyme disease have been associated with B.
burgdorferi-induced inflammation in the central nervous system (CNS). In
this report we investigated which of the primary cell types residing in
the CNS might be functioning to create the inflammatory environment
that, in addition to helping clear the pathogen, could simultaneously be
harming nearby neurons. We report findings that implicate microglia, a
macrophage cell type in the CNS, as the key responders to infection with
B. burgdorferi. We also present evidence indicating that this organism
is not directly toxic to neurons; rather, a bystander effect is
generated whereby the inflammatory surroundings created by microglia in
response to B. burgdorferi may themselves be toxic to neuronal cells.

Citation: Myers TA, Kaushal D, Philipp MT (2009) Microglia Are Mediators
of Borrelia burgdorferi–Induced Apoptosis in SH-SY5Y Neuronal Cells.
PLoS Pathog 5(11): e1000659. doi:10.1371/journal.ppat.1000659

Editor: Jenifer Coburn, Medical College of Wisconsin, United States of
America

Received: May 11, 2009; Accepted: October 19, 2009; Published: November
13, 2009

Copyright: © 2009 Myers et al. This is an open-access article
distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are credited.

Funding: This work was supported by grants NS048952 and RR00164 from the
National Institutes of Health. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the
manuscript.

Competing interests: The authors have declared that no competing
interests exist.

Full text available at this URL

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000659

Microglia Are Mediators of Borrelia burgdorferi–Induced Apoptosis in
SH-SY5Y Neuronal Cells

Tereance A. Myers, Deepak Kaushal, Mario T. Philipp*

Division of Bacteriology & Parasitology, Tulane National Primate
Research Center, Tulane University Health Sciences Center, Louisiana,
United States of America

Abstract