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Inhibition of WNK Kinases in NK Cells Disrupts Cellular Osmoregulation and Control of Tumor Metastasis
1B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Introduction:
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.
Methods:
Using the small-molecule WNK kinase inhibitors WNK463 and WNK-IN-11, we investigated how WNK kinase inhibition affects natural killer (NK) cell physiology.
Results:
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.
Conclusion:
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.
Insights
Pharmacologic inhibition of With-no-lysine (WNK) kinases impairs natural killer (NK) cell function, decreasing their volume, motility, and killing ability. This negatively impacts NK cell-mediated tumor metastasis control.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- With-no-lysine (WNK) kinases regulate blood pressure, electrolyte balance, and cell osmoregulation.
- WNK kinases are potential therapeutic targets for hypertension and stroke.
- The role of WNK kinases in immune cells, particularly NK cells, is largely unknown.
Purpose of the Study:
- To investigate the impact of WNK kinase inhibition on natural killer (NK) cell physiology.
- To explore the mechanisms underlying WNK kinase inhibition effects on NK cells.
- To assess the therapeutic implications of targeting WNK kinases in NK cell-mediated immunity.
Main Methods:
- Utilized small-molecule WNK kinase inhibitors (WNK463 and WNK-IN-11).
- Assessed effects on IL-2-activated NK cell volume, motility, and cytolytic activity.
- Investigated downstream signaling pathways including AMPK, mTOR, Akt, and c-Myc phosphorylation.
- Evaluated NK cell function in a tumor metastasis model in mice.
Main Results:
- WNK kinase inhibition significantly reduced NK cell volume, motility, and cytolytic activity.
- Inhibitors induced autophagy via AMPK activation and mTOR inhibition.
- WNK inhibition altered Akt and c-Myc phosphorylation by disrupting kinase/phosphatase balance.
- Pharmacologic inhibition of WNK kinases impaired NK cell-mediated control of tumor metastasis in vivo.
Conclusions:
- Catalytic activity of WNK kinases is crucial for multiple NK cell functions.
- Pharmacologic inhibition of WNK kinases detrimentally affects NK cell physiology and anti-tumor immunity.
- Targeting WNK kinases may have unintended consequences for immune cell function.
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