Abstract
BackgroundInflammation caused by the Lyme disease spirochete B. burgdorferi is an important factor in the pathogenesis of Lyme neuroborreliosis. Our central hypothesis is that B. burgdorferi can cause disease via the induction of inflammatory mediators such as cytokines and chemokines in glial and neuronal cells. Earlier we demonstrated that interaction of B. burgdorferi with brain parenchyma induces inflammatory mediators in glial cells as well as glial (oligodendrocyte) and neuronal apoptosis using ex vivo and in vivo models of experimentation.MethodsIn this study we evaluated the ability of live B. burgdorferi to elicit inflammation in vitro in differentiated human MO3.13 oligodendrocytes and in differentiated primary human oligodendrocytes, by measuring the concentration of immune mediators in culture supernatants using Multiplex ELISA assays. Concomitant apoptosis was quantified in these cultures by the in situ terminal deoxynucleotidyl transferase mediated UTP nick end labeling (TUNEL) assay and by quantifying active caspase-3 by flow cytometry. The above phenomena were also evaluated after 48 h of stimulation with B. burgdorferi in the presence and absence of various concentrations of the anti-inflammatory drug dexamethasone.ResultsB. burgdorferi induced enhanced levels of the cytokine IL-6 and the chemokines IL-8 and CCL2 in MO3.13 cells as compared to basal levels, and IL-8 and CCL2 in primary human oligodendrocytes, in a dose-dependent manner. These cultures also showed significantly elevated levels of apoptosis when compared with medium controls. Dexamethasone reduced both the levels of immune mediators and apoptosis, also in a manner that was dose dependent.ConclusionsThis finding supports our hypothesis that the inflammatory response elicited by the Lyme disease spirochete in glial cells contributes to neural cell damage. As oligodendrocytes are vital for the functioning and survival of neurons, the inflammation and subsequent apoptosis of oligodendrocytes induced by B. burgdorferi could contribute to the pathogenesis of Lyme neuroborreliosis.
Highlights
Inflammation caused by the Lyme disease spirochete B. burgdorferi is an important factor in the pathogenesis of Lyme neuroborreliosis
Earlier we demonstrated that interaction of B. burgdorferi with brain parenchyma induces inflammatory mediators in glial cells as well as glial and neuronal apoptosis [39]
Pro-inflammatory response induced by B. burgdorferi in MO3.13 oligodendrocytes Live B. burgdorferi spirochetes incubated with differentiated MO3.13 cell cultures for 48 h at a multiplicity of infection (MOI) of 10:1 and 100:1 induced significantly elevated levels of CCL2 (Figure 2A), IL-6 (Figure 2B) and IL-8 (Figure 2C) as compared to the levels induced in medium controls
Summary
Inflammation caused by the Lyme disease spirochete B. burgdorferi is an important factor in the pathogenesis of Lyme neuroborreliosis. Our central hypothesis is that B. burgdorferi can cause disease via the induction of inflammatory mediators such as cytokines and chemokines in glial and neuronal cells. Acute transverse myelitis, caused by inflammatory processes of the spinal cord resulting in LNB patients may experience a wide array of neurological and neuropsychiatric symptoms as a result of white matter inflammation that results in a subacute multiple sclerosis (MS)-like manifestation [12,13]. Inflammatory lesions in the brain and spinal cord show multifocal encephalitis with large areas of demyelination in perivascular white matter commonly associated with the presence of B. burgdorferi DNA [6,20,21,22]. Cells that secrete antibodies to myelin basic protein have been found in CSF of patients with LNB, suggesting damage to oligodendrocytes possibly as a result of demyelination [24]
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