Abstract
Inflammation has long been implicated as a contributor to pathogenesis in many CNS illnesses, including Lyme neuroborreliosis. Borrelia burgdorferi is the spirochete that causes Lyme disease and it is known to potently induce the production of inflammatory mediators in a variety of cells. In experiments where B. burgdorferi was co-cultured in vitro with primary microglia, we observed robust expression and release of IL-6 and IL-8, CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES), but we detected no induction of microglial apoptosis. In contrast, SH-SY5Y (SY) neuroblastoma cells co-cultured with B. burgdorferi expressed negligible amounts of inflammatory mediators and also remained resistant to apoptosis. When SY cells were co-cultured with microglia and B. burgdorferi, significant neuronal apoptosis consistently occurred. Confocal microscopy imaging of these cell cultures stained for apoptosis and with cell type-specific markers confirmed that it was predominantly the SY cells that were dying. Microarray analysis demonstrated an intense microglia-mediated inflammatory response to B. burgdorferi including up-regulation in gene transcripts for TLR-2 and NFκβ. Surprisingly, a pathway that exhibited profound changes in regard to inflammatory signaling was triggering receptor expressed on myeloid cells-1 (TREM1). Significant transcript alterations in essential p53 pathway genes also occurred in SY cells cultured in the presence of microglia and B. burgdorferi, which indicated a shift from cell survival to preparation for apoptosis when compared to SY cells cultured in the presence of B. burgdorferi alone. Taken together, these findings indicate that B. burgdorferi is not directly toxic to SY cells; rather, these cells become distressed and die in the inflammatory surroundings generated by microglia through a bystander effect. If, as we hypothesized, neuronal apoptosis is the key pathogenic event in Lyme neuroborreliosis, then targeting microglial responses may be a significant therapeutic approach for the treatment of this form of Lyme disease.
Highlights
Lyme borreliosis is the most prevalent vector-borne illness in the northern hemisphere [1,2]
We 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
In view of the evidence indicating that microglia were the more robust responders to the inflammatory stimuli of B. burgdorferi (Figure 1), and that molecules other than, or in addition to IL-6, IL-8 and TNF were required to elicit SY cell apoptosis, we further explored the diversity of mediators produced by microglia in response to B. burgdorferi
Summary
Lyme borreliosis is the most prevalent vector-borne illness in the northern hemisphere [1,2]. Upon gaining access to the central nervous system (CNS), B. burgdorferi may induce cerebrospinal fluid pleocytosis, meningoradiculitis and cranial neuritis as well as encephalopathies with neurocognitive abnormalities [3,5,6,11]. This complex process of B. burgdorferiinduced pathology in the CNS has many aspects as yet to be clarified, with reactive inflammation potentially being one of the principal contributors to neuronal dysfunction
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