5-Aminoimidazole-4-carboxamide ribonucleoside-mediated adenosine monophosphate-activated protein kinase activation induces protective innate responses in bacterial endophthalmitis.
5-Aminoimidazole-4-carboxamide ribonucleoside-mediated adenosine monophosphate-activated protein kinase activation induces protective innate responses in bacterial endophthalmitis.
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DOI：
10.1111/cmi.12625
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发表时间：
2016-12
影响因子：
3.4
通讯作者：
Kumar A
中科院分区：
文献类型：
--
作者：
Kumar A;Giri S;Kumar A
视网膜被认为是体内代谢最活跃的组织。然而，能量代谢和视网膜炎症之间的联系，如由微生物感染如眼内炎引起的，仍然未被探索。在这项研究中，使用金黄色葡萄球菌（SA）眼内炎的小鼠模型，我们证明了AMP激活的蛋白激酶α（AMPKα），细胞能量传感器，及其内源性底物乙酰辅酶A羧化酶（ACC）的活性（磷酸化）在SA感染的视网膜下调。玻璃体内注射AMPK激活剂5-氨基咪唑-4-甲酰胺核苷（AICAR）可恢复AMPKα和ACC磷酸化。AICAR治疗通过抑制NF-κB和MAP激酶（p38和JNK）信号转导减少了SA感染眼的细菌负荷和眼内炎症。AICAR的抗炎作用在用AMPK抑制剂化合物C预处理的眼中减弱。SA感染的小胶质细胞和骨髓来源的巨噬细胞（BMDM）的生物能量学（Seahorse）分析揭示了糖酵解的增加，其通过AICAR处理恢复。AICAR还降低了SA诱导的糖酵解基因的表达，包括小胶质细胞、BMDM和小鼠视网膜中的己糖激酶2（HK 2）和葡萄糖转运蛋白1（Glut 1）。有趣的是，AICAR处理增强了培养的小胶质细胞、巨噬细胞和中性粒细胞的细菌吞噬和细胞内杀伤活性。此外，AMPKα1全基因敲除小鼠对SA眼内炎的易感性增加，表现为炎症介质和细菌负荷增加以及视网膜功能降低。总之，这些发现提供了第一个证据，即AMPK激活通过调节能量代谢促进眼内炎中的视网膜先天防御，并且它可以在治疗上靶向治疗眼部感染。
The retina is considered to be the most metabolically active tissue in the body. However, the link between energy metabolism and retinal inflammation, as incited by microbial infection such as endophthalmitis remains unexplored. In this study, using a mouse model of Staphylococcus aureus (SA) endophthalmitis, we demonstrate that the activity (phosphorylation) of AMP-activated protein kinase alpha (AMPKα), a cellular energy sensor, and its endogenous substrate; acetyl-CoA carboxylase (ACC) is downregulated in the SA-infected retina. Intravitreal administration of an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) restored AMPKα and ACC phosphorylation. AICAR treatment reduced both the bacterial burden and intraocular inflammation in SA-infected eyes by inhibiting NF-κB and MAP kinases (p38 and JNK) signaling. The anti-inflammatory effects of AICAR were diminished in eyes pretreated with AMPK inhibitor, Compound C. The bioenergetics (Seahorse) analysis of SA-infected microglia and bone marrow-derived macrophages (BMDM) revealed an increase in glycolysis, which was reinstated by AICAR treatment. AICAR also reduced the expression of SA-induced glycolytic genes, including hexokinase 2 (HK2), and glucose transporter 1 (Glut1) in microglia, BMDM, and the mouse retina. Interestingly, AICAR treatment enhanced the bacterial phagocytic and intracellular killing activities of cultured microglia, macrophages, and neutrophils. Furthermore, AMPKα1 global knockout mice exhibited increased susceptibility towards SA endophthalmitis, as evidenced by increased inflammatory mediators and bacterial burden and reduced retinal function. Together, these findings provide the first evidence that AMPK activation promotes retinal innate defense in endophthalmitis by modulating energy metabolism, and that it can be targeted therapeutically to treat ocular infections.
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影响因子：
2.6
作者：
Hyttinen, Juha M. T.;Petrovski, Goran;Kaarniranta, Kai
通讯作者：
Kaarniranta, Kai
玻染蛋白通过与凋亡细胞以及巨噬细胞的相互作用来抑制胚细胞增多症。
DOI：
10.4049/jimmunol.1200625
发表时间：
2013-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bae HB;Tadie JM;Jiang S;Park DW;Bell CP;Thompson LC;Peterson CB;Thannickal VJ;Abraham E;Zmijewski JW
通讯作者：
Zmijewski JW
影响因子：
3.7
作者：
Ferrer-Martín RM;Martín-Oliva D;Sierra-Martín A;Carrasco MC;Martín-Estebané M;Calvente R;Martín-Guerrero SM;Marín-Teva JL;Navascués J;Cuadros MA
通讯作者：
Cuadros MA
影响因子：
3.9
作者：
Dandapani M;Hardie DG
通讯作者：
Hardie DG
影响因子：
4.4
作者：
Engelbert, M;Gilmore, MS
通讯作者：
Gilmore, MS