PMID- 30112701
OWN - NLM
STAT- MEDLINE
DCOM- 20190312
LR  - 20240204
IS  - 1878-7479 (Electronic)
IS  - 1933-7213 (Print)
IS  - 1878-7479 (Linking)
VI  - 15
IP  - 4
DP  - 2018 Oct
TI  - Inhibition of MyD88 Signaling Skews Microglia/Macrophage Polarization and 
      Attenuates Neuronal Apoptosis in the Hippocampus After Status Epilepticus in 
      Mice.
PG  - 1093-1111
LID - 10.1007/s13311-018-0653-0 [doi]
AB  - Inflammation is implicated in epileptogenesis. Activated microglia and 
      macrophages (MG/MPhi) are found in the brains of patients with epilepsy-related 
      diseases and animal models of epilepsy. It is not yet known how the MG/MPhi 
      activation phenotype affects pathological changes in the brain after a single 
      seizure. In this study, we had 2 main purposes: first, to characterize 
      post-status epilepticus (SE) inflammation by tracking MG/MPhi 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/MPhi 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/MPhi 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/MPhi. Inhibition or 
      gene knockout of MyD88 reduced M1 MG/MPhi and gliosis although increasing M2 MG/MPhi 
      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/MPhi 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.
FAU - Liu, Jin-Tao
AU  - Liu JT
AD  - Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical 
      University, No. 569 Xinsi Road, Xi'an, 710038, China.
AD  - Institute of Neurosciences, Department of Neurobiology and Collaborative 
      Innovation Center for Brain Science, The Fourth Military Medical University, No. 
      169, Changle West Road, Xi'an, 710032, China.
AD  - Department of Orthopedics, The 413th Hospital of the Chinese People's Liberation 
      Army, Zhoushan, 316000, China.
FAU - Wu, Sheng-Xi
AU  - Wu SX
AD  - Institute of Neurosciences, Department of Neurobiology and Collaborative 
      Innovation Center for Brain Science, The Fourth Military Medical University, No. 
      169, Changle West Road, Xi'an, 710032, China.
FAU - Zhang, Hua
AU  - Zhang H
AD  - Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical 
      University, No. 569 Xinsi Road, Xi'an, 710038, China. zhanghua2016@sohu.com.
FAU - Kuang, Fang
AU  - Kuang F
AD  - Institute of Neurosciences, Department of Neurobiology and Collaborative 
      Innovation Center for Brain Science, The Fourth Military Medical University, No. 
      169, Changle West Road, Xi'an, 710032, China. kuangf@fmmu.edu.cn.
LA  - eng
GR  - 81671217/National Natural Science Foundation of China/International
GR  - 81271433/National Natural Science Foundation of China/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neurotherapeutics
JT  - Neurotherapeutics : the journal of the American Society for Experimental 
      NeuroTherapeutics
JID - 101290381
RN  - 0 (Cytokines)
RN  - 0 (Myd88 protein, mouse)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Peptides)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
RN  - 01MI4Q9DI3 (Pilocarpine)
RN  - 9FN79X2M3F (Lithium)
SB  - IM
MH  - Animals
MH  - Apoptosis/genetics/*physiology
MH  - Cell Polarity/genetics
MH  - Cytokines/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression Regulation, Archaeal/drug effects/genetics
MH  - Hippocampus/*metabolism/pathology
MH  - In Situ Nick-End Labeling
MH  - Lithium/toxicity
MH  - Macrophages/*pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Microglia/*pathology
MH  - Myeloid Differentiation Factor 88/*antagonists & inhibitors/chemistry/deficiency
MH  - Neurons/*pathology
MH  - Peptides/therapeutic use
MH  - Pilocarpine/toxicity
MH  - Signal Transduction/*genetics
MH  - Status Epilepticus/chemically induced/genetics/*pathology
MH  - Toll-Like Receptor 4/metabolism
PMC - PMC6277303
OTO - NOTNLM
OT  - Hippocampus
OT  - Microglia/macrophage polarization
OT  - MyD88
OT  - Neuroinflammation
OT  - Status epilepticus
COIS- The authors declare that they have no conflicts of interest.
EDAT- 2018/08/17 06:00
MHDA- 2019/03/13 06:00
PMCR- 2018/08/15
CRDT- 2018/08/17 06:00
PHST- 2018/08/17 06:00 [pubmed]
PHST- 2019/03/13 06:00 [medline]
PHST- 2018/08/17 06:00 [entrez]
PHST- 2018/08/15 00:00 [pmc-release]
AID - S1878-7479(23)01035-8 [pii]
AID - 653 [pii]
AID - 10.1007/s13311-018-0653-0 [doi]
PST - ppublish
SO  - Neurotherapeutics. 2018 Oct;15(4):1093-1111. doi: 10.1007/s13311-018-0653-0.