Atorvastatin prevents age-related and amyloid-β-induced microglial activation by blocking interferon-γ release from natural killer cells in the brain

被引:28
作者
Lyons, Anthony [1 ]
Murphy, Kevin J. [1 ]
Clarke, Rachael [1 ]
Lynch, Marina A. [1 ]
机构
[1] Trinity Coll Dublin, Dept Physiol, Inst Neurosci, Dublin 2, Ireland
基金
爱尔兰科学基金会;
关键词
COA REDUCTASE INHIBITOR; IN-VIVO; EXPRESSION; CYTOTOXICITY; MACROPHAGES; MODULATION; RECEPTOR; PEPTIDE; DISEASE; RATS;
D O I
10.1186/1742-2094-8-27
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background: Microglial function is modulated by several factors reflecting the numerous receptors expressed on the cell surface, however endogenous factors which contribute to the age-related increase in microglial activation remain largely unknown. One possible factor which may contribute is interferon-gamma (IFN gamma). IFN gamma has been shown to increase in the aged brain and potently activates microglia, although its endogenous cell source in the brain remains unidentified. Methods: Male Wistar rats were used to assess the effect of age and amyloid-beta (A beta) on NK cell infiltration into the brain. The effect of the anti-inflammatory compound, atorvastatin was also assessed under these conditions. We measured cytokine and chemokine (IFN gamma, IL-2, monocyte chemoattractant protein-1 (MCP-1) and IFN gamma-induced protein 10 kDa (IP-10)), expression in the brain by appropriate methods. We also looked at NK cell markers, CD161, NKp30 and NKp46 using flow cytometry and western blot. Results: Natural killer (NK) cells are a major source of IFN gamma in the periphery and here we report the presence of CD161(+) NKp30(+) cells and expression of CD161 and NKp46 in the brain of aged and Ab-treated rats. Furthermore, we demonstrate that isolated CD161(+) cells respond to interleukin-2 (IL-2) by releasing IFN gamma. Atorvastatin, the HMG-CoA reductase inhibitor, attenuates the increase in CD161 and NKp46 observed in hippocampus of aged and A beta-treated rats. This was paralleled by a decrease in IFNg, markers of microglial activation and the chemokines, MCP-1 and IP-10 which are chemotactic for NK cells. Conclusions: We propose that NK cells contribute to the age-related and A beta-induced neuroinflammatory changes and demonstrate that these changes can be modulated by atorvastatin treatment.
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页数:10
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