Microglial phenotypes in the human epileptic temporal lobe

Abstract

Microglia, immune cells of the brain, are highly plastic and possess multiple functional phenotypes. Differences in phenotype in different regions and different states of epileptic human brain have been little studied. Here we use transcriptomics, anatomy, imaging of living cells and ELISA measurements of cytokine release to examine microglia from patients with temporal lobe epilepsies. Two distinct microglial phenotypes were explored. First we asked how microglial phenotype differs between regions of high and low neuronal loss in the same brain. Secondly we asked how microglial phenotype is changed by a recent seizure. In sclerotic areas with few neurons, microglia have an amoeboid rather than ramified shape, express activation markers and respond faster to purinergic stimuli. The repairing interleukin, IL-10, regulates the basal phenotype of microglia in the CA1 and CA3 regions with neuronal loss and gliosis. To understand changes in phenotype induced by a seizure, we estimated the delay from the last seizure until tissue collection from changes in reads for immediate early gene transcripts. Pseudotime ordering of this data was validated by comparison with results from kainate-treated mice. It revealed a local and transient phenotype in which microglia secrete the human interleukin CXCL8, IL-1B and other cytokines. This secretory response is mediated in part via the NRLP3 inflammasome.

Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice

“…As miR-22 −/− mice experienced more spontaneous seizures than ASO-treated mice, microglial rather than astroglial increases may be a cellular correlate of the cumulative or overall burden of spontaneous seizures in this model. This would be consistent with microglia responses and recent seizures in humans [30], the use of microglial-based brain imaging as epilepsy biomarkers [31,32] and experimental evidence that microglia changes are epileptogenic [33]. Notably, the microglial changes may be unrelated to inflammatory responses since microglial perform other roles including synaptic pruning [34].…”

Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice

“…As miR-22 -/mice experienced more spontaneous seizures than ASO-treated mice, microglial rather than astroglial increases may be a cellular correlate of the cumulative or overall burden of spontaneous seizures in this model. This would be consistent with microglia responses and recent seizures in humans [30], the use of microglial-based brain imaging as epilepsy biomarkers [31,32] and experimental evidence that microglia changes are epileptogenic [33]. Notably, the microglial changes may be unrelated to in ammatory responses since microglial perform other roles including synaptic pruning [34].…”

Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice

“…As miR-22 -/mice experienced more spontaneous seizures than ASO-treated mice, microglial rather than astroglial increases may be a cellular correlate of the cumulative or overall burden of spontaneous seizures in this model. This would be consistent with microglia responses and recent seizures in humans [29], the use of microglial-based brain imaging as epilepsy biomarkers [30,31] and experimental evidence that microglia changes are epileptogenic [32].…”