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CKLF1 Aggravates Focal Cerebral Ischemia Injury at Early Stage Partly by Modulating Microglia/Macrophage Toward M1 Polarization Through CCR4.
- Source :
-
Cellular and molecular neurobiology [Cell Mol Neurobiol] 2019 Jul; Vol. 39 (5), pp. 651-669. Date of Electronic Publication: 2019 Apr 13. - Publication Year :
- 2019
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Abstract
- CKLF1 is a chemokine with increased expression in ischemic brain, and targeting CKLF1 has shown therapeutic effects in cerebral ischemia model. Microglia/macrophage polarization is a mechanism involved in poststroke injury expansion. Considering the quick and obvious response of CKLF1 and expeditious evolution of stroke lesions, we focused on the effects of CKLF1 on microglial/macrophage polarization at early stage of ischemic stroke (IS). The present study is to investigate the CKLF1-mediated expression of microglia/macrophage phenotypes in vitro and in vivo, discussing the involved pathway. Primary microglia culture was used in vitro, and mice transient middle cerebral artery occlusion (MCAO) model was adopted to mimic IS. CKLF1 was added to the primary microglia for 24 h, and we found that CKLF1 modulated primary microglia skew toward M1 phenotype. In mice transient IS model, CKLF1 was stereotactically microinjected to the lateral ventricle of ischemic hemisphere. CKLF1 aggravated ischemic injury, accompanied by promoting microglia/macrophage toward M1 phenotypic polarization. Increased expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines were observed in mice subjected to cerebral ischemia and administrated with CKLF1. CKLF1 <superscript>-/-</superscript> mice were used to confirm the effects of CKLF1. CKLF1 <superscript>-/-</superscript> mice showed lighter cerebral damage and decreased M1 phenotype of microglia/macrophage compared with the WT control subjected to cerebral ischemia. Moreover, NF-κB activation enhancement was detected in CKLF1 treatment group. Our results demonstrated that CKLF1 is an important mediator that skewing microglia/macrophage toward M1 phenotype at early stage of cerebral ischemic injury, which further deteriorates followed inflammatory response, contributing to early expansion of cerebral ischemia injury. Targeting CKLF1 may be a novel way for IS therapy.
- Subjects :
- Animals
Animals, Newborn
Brain pathology
Disease Models, Animal
Infarction, Middle Cerebral Artery pathology
Inflammation pathology
Male
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Phenotype
Brain Ischemia metabolism
Brain Ischemia pathology
Cell Polarity
Chemokines metabolism
Macrophages pathology
Microglia pathology
Receptors, CCR4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1573-6830
- Volume :
- 39
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cellular and molecular neurobiology
- Publication Type :
- Academic Journal
- Accession number :
- 30982091
- Full Text :
- https://doi.org/10.1007/s10571-019-00669-5