Inhibition of MyD88 Signaling Skews Microglia/Macrophage Polarization and Attenuates Neuronal Apoptosis in the Hippocampus After Status Epilepticus in Mice

Abstract

Inflammation is implicated in epileptogenesis. Activated microglia and macrophages (MG/MΦ) are found in the brains of patients with epilepsy-related diseases and animal models of epilepsy. It is not yet known how the MG/MΦ activation phenotype affects pathological changes in the brain after a single seizure. In this study, we had 2 main purposes: first, to characterize poststatus epilepticus (SE) inflammation by tracking MG/MΦ polarization, and, second, to explore the role of an innate immune receptor adaptor protein, namely, myeloid differentiation primary response gene 88 (MyD88), in the induction of SE in a mouse model. A lithium-pilocarpine model of seizure conditions was generated in C57BL/6 mice. The intensity and distribution of MG/ MΦ polarization were tracked by fluorescent immunohistochemistry and Western blotting for the polarization markers inducible nitrogen oxygenized synthase, arginase-1, CD163, and mannose receptor. We observed steadily increasing M1 MG/MΦ along with MyD88 signal upregulation after SE in the hippocampi of mice, whereas the M2 marker arginase-1 was localized mainly in astrocytes rather than in MG/MΦ. Inhibition or gene knockout of MyD88 reduced M1 MG/MΦ and gliosis although increasing M2 MG/MΦ in the hippocampi of SE mice. MyD88 inhibition also augmented glutamate transporter 1 expression and reduced N-methyl-D-aspartate receptor NR1 subunit expression in the hippocampus to protect pyramidal neurons from apoptosis. These data suggest that MG/MΦ polarization after SE impacts the pathological outcome of the hippocampus via MyD88 signaling and point to MyD88 as a potential neuroprotective target for epilepsy therapy.

LncRNA RMST activates TAK1‐mediated NF‐κB signaling and promotes activation of microglial cells via competitively binding with hnRNPK

“…Previous studies have indicated that microglial M1 polarization leads to neuronal death and extensive gliosis . To ascertain the relationship between RMST‐mediated microglia polarization and neuronal apoptosis, the culture supernatant of BV2 cells transfected with Lv‐RMST or Lv‐sh‐RMST following treatment of OGD was used as condition medium of HT‐22 hippocampal neuron cells.…”

Dynorphin activation of kappa opioid receptor promotes microglial polarization toward M2 phenotype via TLR4/NF-κB pathway

“…(TNF)-α [6]. The M2 phenotype is characterized by increased expression of several proteins such as arginase-1 (Arg-1) and mannose receptor (MR/CD206), as well as increased production of anti-inflammatory cytokines IL-4 and IL-10 [1,3]. Convincing evidence has suggested that the pro-and anti-inflammatory states of microglia indeed determine the outcomes of many CNS diseases, including epilepsy.…”

Time-sequential Neuroinflammatory Response After Organophosphate-induced Status Epilepticus

“…Compared to RT-qPCR on cerebral tissue, RT-qPCR after cell sorting allow to identify the cellular origin of in ammatory genes up-regulation and confers increased sensibility by concentrating a speci c cell type. Discussions on the existence of differential M1 and M2 phenotypes in microglial cells is still existing and M1/M2 dichotomy is certainly an oversimpli cation [24][25][26][27]. However diverse opposing impacts of activated microglia on neuronal damage have been demonstrated and modulation of microglial cells polarization towards a M2 phenotype have been described as bene cial [24,25,[28][29][30].…”