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Human NK Cell Cytoskeletal Dynamics and Cytotoxicity Are Regulated by LIM Kinase
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-07-08 , DOI: 10.4049/jimmunol.2000186
Melody G Duvall 1, 2 , Mary E Fuhlbrigge 1 , Roisin B Reilly 1 , Katherine H Walker 1 , Ayşe Kılıç 1, 3 , Bruce D Levy 4
Affiliation  

Key Points Dexamethasone impairs NK cell cytotoxicity by suppressing LIMK F-actin regulation. Lipoxin A4 induces LIMK to promote lytic granule trafficking and NK cell killing. NK cells provide immune surveillance and host protection against viruses and tumors through their cytotoxic effector function. Cytoskeletal rearrangement is necessary for NK cell lytic granule trafficking and immune synapse formation to trigger apoptosis of targeted cells. LIM kinase (LIMK) regulates F-actin remodeling by phosphorylating cofilin to inhibit actin severing and depolymerization. In this study, in human NK cells, the glucocorticoid dexamethasone downregulated LIMK expression, F-actin accumulation at the immune synapse, lytic granule trafficking, and cytotoxicity. In contrast, the specialized proresolving mediator lipoxin A4 promoted NK cell LIMK expression, lytic granule polarization to the immune synapse and cytotoxicity. Using a LIMK inhibitor, we show that LIMK activity is necessary for NK cell cytotoxicity, including lipoxin A4’s proresolving actions. Together, our findings identify LIMK as an important control mechanism for NK cell cytoskeletal rearrangement that is differentially regulated by glucocorticoids and specialized proresolving mediators to influence NK cell cytotoxicity.

中文翻译:

人类 NK 细胞骨架动力学和细胞毒性受 LIM 激酶调节

关键点地塞米松通过抑制 LIMK F-肌动蛋白调节来削弱 NK 细胞的细胞毒性。Lipoxin A4 诱导 LIMK 促进裂解颗粒运输和 NK 细胞杀伤。NK 细胞通过其细胞毒性效应子功能提供免疫监视和宿主针对病毒和肿瘤的保护。细胞骨架重排是 NK 细胞裂解颗粒运输和免疫突触形成所必需的,以触发靶细胞的凋亡。LIM 激酶 (LIMK) 通过磷酸化 cofilin 以抑制肌动蛋白切断和解聚来调节 F-肌动蛋白重塑。在这项研究中,在人类 NK 细胞中,糖皮质激素地塞米松下调 LIMK 表达、免疫突触中 F-肌动蛋白的积累、裂解颗粒运输和细胞毒性。相比之下,专门的促分解介质脂氧素 A4 促进了 NK 细胞 LIMK 的表达,裂解颗粒对免疫突触的极化和细胞毒性。使用 LIMK 抑制剂,我们表明 LIMK 活性是 NK 细胞细胞毒性所必需的,包括脂氧素 A4 的促分解作用。总之,我们的研究结果将 LIMK 确定为 NK 细胞骨架重排的重要控制机制,该机制受糖皮质激素和专门的促分解介质的差异调节,以影响 NK 细胞的细胞毒性。
更新日期:2020-07-08
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