| Autor: |
Tianwen Gao, Syed Ali Raza, Supriya Ramesha, Ngozi V. Nwabueze, Amelia J. Tomkins, Lihong Cheng, Hailian Xiao, Manuel Yepes, Srikant Rangaraju |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
|
| Zdroj: |
Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-11 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
1742-2094 |
| DOI: |
10.1186/s12974-019-1510-8 |
| Popis: |
Abstract Background Microglia and CNS-infiltrating monocytes/macrophages (CNS-MPs) perform pro-inflammatory and protective anti-inflammatory functions following ischemic stroke. Selective inhibition of pro-inflammatory responses can be achieved by Kv1.3 channel blockade, resulting in a lower infarct size in the transient middle cerebral artery occlusion (tMCAO) model. Whether beneficial effects of Kv1.3 blockers are mediated by targeting microglia or CNS-infiltrating monocytes/macrophages remains unclear. Methods In the 30-min tMCAO mouse model, we profiled functional cell-surface Kv1.3 channels and phagocytic properties of acutely isolated CNS-MPs at various timepoints post-reperfusion. Kv1.3 channels were flow cytometrically detected using fluorescein-conjugated Kv1.3-binding peptide ShK-F6CA as well as by immunohistochemistry. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was performed to measure Kv1.3 (Kcna3) and Kir2.1 (Kcnj2) gene expression. Phagocytosis of 1-μm microspheres by acutely isolated CNS-MPs was measured by flow cytometry. Results In flow cytometric assays, Kv1.3 channel expression by CD11b+ CNS-MPs was increased between 24 and 72 h post-tMCAO and decreased by 7 days post-tMCAO. Increased Kv1.3 expression was restricted to CD11b+CD45lowLy6clow (microglia) and CD11b+CD45highLy6Clow CNS-MPs but not CD11b+CD45highLy6chigh inflammatory monocytes/macrophages. In immunohistochemical studies, Kv1.3 protein expression was increased in Iba1+ microglia at 24-48 h post-tMCAO. No change in Kv1.3 mRNA in CNS-MPs was observed following tMCAO. Conclusions We conclude that resident microglia and a subset of CD45highLy6clow CNS-MPs are the likely cellular targets of Kv1.3 blockers and the delayed phase of neuroinflammation is the optimal therapeutic window for Kv1.3 blockade in ischemic stroke. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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