B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
J Innate Immun. 2024;16(1):451-469. doi: 10.1159/000540744. Epub 2024 Sep 12.
The serine/threonine with-no-lysine (WNK) kinase family function in blood pressure control, electrolyte homeostasis, and cellular osmoregulation. These kinases and their downstream effectors are considered promising therapeutic targets in hypertension and stroke. However, the role of WNK kinases in immune cells remains poorly understood.
Using the small-molecule WNK kinase inhibitors WNK463 and WNK-IN-11, we investigated how WNK kinase inhibition affects natural killer (NK) cell physiology.
WNK kinase inhibition with WNK463 or WNK-IN-11 significantly decreased IL-2-activated NK cell volume, motility, and cytolytic activity. Treatment of NK cells with these inhibitors induced autophagy by activating AMPK and inhibiting mTOR signaling. Moreover, WNK kinase inhibition increased phosphorylation of Akt and c-Myc by misaligning activity of activating kinases and inhibitory phosphatases. Treatment of tumor-bearing mice with WNK463 impaired tumor metastasis control by adoptively transferred NK cells.
The catalytic activity of WNK kinases has a critical role of multiple aspects of NK cell physiology and their pharmacologic inhibition negatively impacts NK cell function.
丝氨酸/苏氨酸不含赖氨酸（WNK）激酶家族在血压控制、电解质稳态和细胞渗透调节中发挥作用。这些激酶及其下游效应物被认为是高血压和中风的有前途的治疗靶点。然而，WNK 激酶在免疫细胞中的作用仍知之甚少。
我们使用小分子 WNK 激酶抑制剂 WNK463 和 WNK-IN-11，研究了 WNK 激酶抑制如何影响自然杀伤 (NK) 细胞的生理学。
WNK463 或 WNK-IN-11 的 WNK 激酶抑制显著降低了 IL-2 激活的 NK 细胞体积、运动性和细胞溶解活性。用这些抑制剂处理 NK 细胞通过激活 AMPK 和抑制 mTOR 信号诱导自噬。此外，WNK 激酶抑制通过错误排列激活激酶和抑制性磷酸酶的活性来增加 Akt 和 c-Myc 的磷酸化。用 WNK463 治疗荷瘤小鼠会削弱过继转移的 NK 细胞对肿瘤转移的控制。
WNK 激酶的催化活性对 NK 细胞生理学的多个方面具有关键作用，其药理学抑制对 NK 细胞功能产生负面影响。
