Background In the healthy central nervous system (CNS), microglia are found in a homeostatic state and peripheral macrophages are absent from the brain. Microglia play key roles in maintaining CNS homeostasis and acting as first responders to infection and inflammation, and peripheral macrophages infiltrate the CNS during neuroinflammation. Due to their distinct origins and functions, discrimination between these cell populations is essential to the comprehension of neuroinflammatory disorders. Studies comparing the gene profiles of microglia and peripheral macrophages, or macrophages in vitro-derived from bone marrow, under non-infectious conditions of the CNS, have revealed valuable microglial-specific genes. However, studies comparing gene profiles between CNS-infiltrating macrophages and microglia, when both are isolated from the CNS during viral-induced neuroinflammation, are lacking. Methods We isolated, via flow cytometry, microglia and infiltrating macrophages from the brains of Theiler’s murine encephalomyelitis virus-infected C57BL/6 J mice and used RNA-Seq, followed by validation with qPCR, to examine the differential transcriptional profiles of these cells. We utilized primary literature defining subcellular localization to determine whether or not particular proteins extracted from the transcriptional profiles were expressed at the cell surface. The surface expression and cellular specificity of triggering receptor expressed on myeloid cells 1 (TREM-1) protein were examined via flow cytometry. We also examined the immune response gene profile within the transcriptional profiles of these isolated microglia and infiltrating macrophages. Results We have identified and validated new microglial- and macrophage-specific genes, encoding cell surface proteins, expressed at the peak of neuroinflammation. TREM-1 protein was confirmed to be expressed by infiltrating macrophages, not microglia, at the peak of neuroinflammation. We also identified both unique and redundant immune functions, through examination of the immune response gene profiles, of microglia and infiltrating macrophages during neurotropic viral infection. Conclusions The differential expression of cell surface-specific genes during neuroinflammation can potentially be used to discriminate between microglia and macrophages as well as provide a resource that can be further utilized to target and manipulate specific cell responses during neuroinflammation. Electronic supplementary material The online version of this article (10.1186/s12974-019-1545-x) contains supplementary material, which is available to authorized users.

Mouse models are great tools to study the mechanisms of disease development. Theiler’s murine encephalomyelitis virus is used in two distinct viral infection mouse models to study the human diseases multiple sclerosis (MS) and epilepsy. Intracerebral (i.c.) infection of the SJL/J mouse strain results in persistent viral infection of the central nervous system and a MS-like disease, while i.c. infection of the C57BL/6J mouse strain results in acute seizures and epilepsy. Our understanding of how the immune system contributes to the development of two disparate diseases caused by the same virus is presented.

Epidemiological studies have revealed a significantly reduced risk of Parkinson's disease (PD) among coffee and tobacco users, although it is unclear whether these correlations reflect neuroprotective/symptomatic effects of these agents or preexisting differences in the brains of tobacco and coffee users. Here, we report that coffee and tobacco, but not caffeine or nicotine, are neuroprotective in fly PD models. We further report that decaffeinated coffee and nicotine-free tobacco are as neuroprotective as their caffeine and nicotine-containing counterparts and that the neuroprotective effects of decaffeinated coffee and nicotine-free tobacco are also evident in Drosophila models of Alzheimer's disease and polyglutamine disease. Finally, we report that the neuroprotective effects of decaffeinated coffee and nicotinefree tobacco require the cytoprotective transcription factor Nrf2 and that a known Nrf2 activator in coffee, cafestol, is also able to confer neuroprotection in our fly models of PD. Our findings indicate that coffee and tobacco contain Nrf2-activating compounds that may account for the reduced risk of PD among coffee and tobacco users. These compounds represent attractive candidates for therapeutic intervention in PD and perhaps other neurodegenerative diseases.

Seizures occur due to an imbalance between excitation and inhibition, with the balance tipping towards excitation, and glutamate is the predominant excitatory neurotransmitter in the central nervous system of mammals. Since upregulation of expression and/or function of glutamate receptors can contribute to seizures we determined the effects of three antagonists, NBQX, GYKI-52466 and MK 801, of the various ionotropic glutamate receptors, AMPA, NMDA and KA, on acute seizure development in the Theiler’s murine encephalomyelitis virus (TMEV)-induced seizure model. We found that only NBQX had an effect on acute seizure development, resulting in a significantly higher number of mice experiencing seizures, an increase in the number of seizures per mouse, a greater cumulative seizure score per mouse and a significantly higher mortality rate among the mice. Although NBQX has previously been shown to be a potent anticonvulsant in animal seizure models, seizures induced by electrical stimulation, drug administration or as a result of genetic predisposition may differ greatly in terms of mechanism of seizure development from our virus-induced seizure model, which could explain the opposite, proconvulsant effect of NBQX observed in the TMEV-induced seizure model.

Viral encephalitis markedly increases the risk for the development of epilepsy. The Theiler’s murine encephalomyelitis virus (TMEV)-induced model of seizures/epilepsy is a murine model of both viral-induced seizures/epilepsy and human Temporal Lobe Epilepsy. The inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α have been shown to play a role in seizure development in the TMEV-induced model of seizures/epilepsy, and infiltrating macrophages along with microglia have been shown to be major producers of these cytokines. The metabotropic glutamate receptor 5 (mGluR5) is a G-protein coupled receptor that has been shown to reduce IL-6 and TNF-α and to provide neuroprotection in other disease models. Therefore, we hypothesized that stimulation of mGluR5 would not only reduce seizures but attenuate IL-6 and TNF-α production in microglia and macrophages in the TMEV model. We found that pharmacological stimulation of mGluR5 with the selective positive allosteric modulator VU0360172 not only reduced acute seizure outcomes, but also reduced the percent of microglia and macrophages producing TNF-α 3 days post infection. Furthermore, treatment with VU0360172 did not alter the level of viral antigen, compared to controls, showing that this treatment does not compromise viral clearance. These results establish that mGluR5 may represent a therapeutic target in the TMEV-induced model of seizures/epilepsy.