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Exp Neurol ; 295: 184-193, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28601603

RESUMO

Microglia-mediated neuroinflammation is widely associated with seizures and epilepsy. Although microglial cells are professional phagocytes, less is known about the status of this phenotype in epilepsy. Recent evidence supports that phagocytosis-associated molecules from the classical complement (C1q-C3) play novel roles in microglia-mediated synaptic pruning. Interestingly, in human and experimental epilepsy, altered mRNA levels of complement molecules were reported. Therefore, to identify a potential role for complement and microglia in the synaptodendritic pathology of epilepsy, we determined the protein levels of classical complement proteins (C1q-C3) along with other phagocytosis signaling molecules in human epilepsy. Cortical brain samples surgically resected from patients with refractory epilepsy (RE) and non-epileptic lesions (NE) were examined. Western blotting was used to determine the levels of phagocytosis signaling proteins such as the complements C1q and C3, MerTK, Trem2, and Pros1 along with cleaved-caspase 3. In addition, immunostaining was used to determine the distribution of C1q and co-localization to microglia and dendrites. We found that the RE samples had significantly increased protein levels of C1q (p=0.034) along with those of its downstream activation product iC3b (p=0.027), and decreased levels of Trem2 (p=0.045) and Pros1 (p=0.005) when compared to the NE group. Protein levels of cleaved-caspase 3 were not different between the groups (p=0.695). In parallel, we found C1q localization to microglia and dendrites in both NE and RE samples, and also observed substantial microglia-dendritic interactions in the RE tissue. These data suggest that aberrant phagocytic signaling occurs in human refractory epilepsy. It is likely that alteration of phagocytic pathways may contribute to unwanted elimination of cells/synapses and/or impaired clearance of dead cells. Future studies will investigate whether altered complement signaling contributes to the hyperexcitability that result in epilepsy.


Assuntos
Ativação do Complemento/genética , Via Clássica do Complemento , Epilepsia/genética , Fagocitose/genética , Células Cultivadas , Córtex Cerebral/patologia , Complemento C1q/biossíntese , Complemento C1q/genética , Complemento C3/biossíntese , Complemento C3/genética , Via Clássica do Complemento/genética , Dendritos/genética , Dendritos/metabolismo , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/patologia , Humanos , Microglia/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/biossíntese , Proteína Quinase 1 Ativada por Mitógeno/genética
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