Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Division of Critical Care Medicine, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115; and.
J Immunol. 2020 Aug 1;205(3):801-810. doi: 10.4049/jimmunol.2000186. Epub 2020 Jul 8.
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 A 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 A'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.
自然杀伤 (NK) 细胞通过其细胞毒性效应功能提供免疫监视和宿主对病毒和肿瘤的保护。细胞骨架重排对于 NK 细胞溶酶体颗粒的运输和免疫突触的形成以触发靶细胞凋亡是必要的。LIM 激酶 (LIMK) 通过磷酸化原肌球蛋白来抑制肌动蛋白的切割和解聚，从而调节 F-actin 的重塑。在这项研究中，在人 NK 细胞中，糖皮质激素地塞米松下调了 LIMK 的表达、免疫突触处 F-actin 的积累、溶酶体颗粒的运输和细胞毒性。相比之下，特异性促炎介质脂氧素 A 促进了 NK 细胞 LIMK 的表达、溶酶体颗粒向免疫突触的极化和细胞毒性。使用 LIMK 抑制剂，我们表明 LIMK 活性对于 NK 细胞的细胞毒性是必需的，包括脂氧素 A 的促解决作用。总之，我们的研究结果确定 LIMK 是 NK 细胞细胞骨架重排的一个重要控制机制，其受糖皮质激素和特异性促炎介质的差异调节，从而影响 NK 细胞的细胞毒性。
