Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration
<h3>Background</h3><p dir="ltr"><u>TRPM4</u> is a broadly expressed, calcium-activated, <u>monovalent</u> cation channel that regulates <u>immune cell</u> function in mice and cell lines. Clinically, however, partial loss- or gain-of-fu...
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| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , , , , , , , , , , , , , , |
| منشور في: |
2024
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| الموضوعات: | |
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| الملخص: | <h3>Background</h3><p dir="ltr"><u>TRPM4</u> is a broadly expressed, calcium-activated, <u>monovalent</u> cation channel that regulates <u>immune cell</u> function in mice and cell lines. Clinically, however, partial loss- or gain-of-function mutations in <i><u>TRPM4</u></i> lead to <u>arrhythmia </u>and<u> heart disease</u>, with no documentation of<u> immunologic disorders.</u> </p><h3>Objective</h3><p dir="ltr">To characterize functional cellular mechanisms underlying the <u>immune dysregulation</u> phenotype in a <u>proband</u> with a mutated <i><u>TRPM4 </u></i>gene. </p><h3>Methods</h3><p dir="ltr">We employed a combination of biochemical, cell biological, imaging, <u>omics</u> analyses, flow cytometry, and gene editing approaches. </p><h3>Results</h3><p dir="ltr">We report the first human cases to our knowledge with complete loss of the <u>TRPM4 channel</u>, leading to <u>immune dysregulation</u> with frequent bacterial and <u>fungal infections</u>. Single-cell and <u>bulk RNA sequencing</u> point to altered expression of genes affecting cell migration, specifically in <u>monocytes</u>. Inhibition of TRPM4 in <u>T cells</u> and the THP-1 monocyte cell line reduces migration. More importantly, primary <u>T cells</u> and <u>monocytes</u> from TRPM4 patients migrate poorly. Finally,<u> CRISPR </u>knockout of <i><u>TRPM4 </u></i>in THP-1 cells greatly reduces their migration potential. </p><h3>Conclusion</h3><p dir="ltr">Our results demonstrate that TRPM4 plays a critical role in regulating<u> immune cell </u>migration, leading to increased susceptibility to infections.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Allergy and Clinical Immunology<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.jaci.2024.02.026" target="_blank">https://dx.doi.org/10.1016/j.jaci.2024.02.026</a></p> |
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