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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2024
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| _version_ | 1864513542592397312 |
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| author | Fang Yu (156838) |
| author2 | Satanay Hubrack (194364) Christophe M. Raynaud (102751) Asha Elmi (9592371) Rafah Mackeh (14151225) Nourhen Agrebi (14151222) Gaurav Thareja (459188) Abdelaziz Belkadi (21842165) Hesham Al Saloos (21842168) Ayeda Abdulsalam Ahmed (10327970) Saleema C. Purayil (21459884) Yasmin A. Mohamoud (10671696) Karsten Suhre (67967) Charbel Abi Khalil (781797) Frank Schmidt (207186) Bernice Lo (3441317) Amel Hassan (14151231) Khaled Machaca (194372) |
| author2_role | author author author author author author author author author author author author author author author author author |
| author_facet | Fang Yu (156838) Satanay Hubrack (194364) Christophe M. Raynaud (102751) Asha Elmi (9592371) Rafah Mackeh (14151225) Nourhen Agrebi (14151222) Gaurav Thareja (459188) Abdelaziz Belkadi (21842165) Hesham Al Saloos (21842168) Ayeda Abdulsalam Ahmed (10327970) Saleema C. Purayil (21459884) Yasmin A. Mohamoud (10671696) Karsten Suhre (67967) Charbel Abi Khalil (781797) Frank Schmidt (207186) Bernice Lo (3441317) Amel Hassan (14151231) Khaled Machaca (194372) |
| author_role | author |
| dc.creator.none.fl_str_mv | Fang Yu (156838) Satanay Hubrack (194364) Christophe M. Raynaud (102751) Asha Elmi (9592371) Rafah Mackeh (14151225) Nourhen Agrebi (14151222) Gaurav Thareja (459188) Abdelaziz Belkadi (21842165) Hesham Al Saloos (21842168) Ayeda Abdulsalam Ahmed (10327970) Saleema C. Purayil (21459884) Yasmin A. Mohamoud (10671696) Karsten Suhre (67967) Charbel Abi Khalil (781797) Frank Schmidt (207186) Bernice Lo (3441317) Amel Hassan (14151231) Khaled Machaca (194372) |
| dc.date.none.fl_str_mv | 2024-09-04T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.jaci.2024.02.026 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Loss_of_the_TRPM4_channel_in_humans_causes_immune_dysregulation_with_defective_monocyte_migration/29715671 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Immunology TRPM4 immune dysregulation monocyte migration loss of function infections |
| dc.title.none.fl_str_mv | Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <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> |
| eu_rights_str_mv | openAccess |
| id | Manara2_984c8e54057e428794b53e2e94d2e0a1 |
| identifier_str_mv | 10.1016/j.jaci.2024.02.026 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/29715671 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migrationFang Yu (156838)Satanay Hubrack (194364)Christophe M. Raynaud (102751)Asha Elmi (9592371)Rafah Mackeh (14151225)Nourhen Agrebi (14151222)Gaurav Thareja (459188)Abdelaziz Belkadi (21842165)Hesham Al Saloos (21842168)Ayeda Abdulsalam Ahmed (10327970)Saleema C. Purayil (21459884)Yasmin A. Mohamoud (10671696)Karsten Suhre (67967)Charbel Abi Khalil (781797)Frank Schmidt (207186)Bernice Lo (3441317)Amel Hassan (14151231)Khaled Machaca (194372)Biological sciencesGeneticsBiomedical and clinical sciencesImmunologyTRPM4immune dysregulationmonocytemigrationloss of functioninfections<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>2024-09-04T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.jaci.2024.02.026https://figshare.com/articles/journal_contribution/Loss_of_the_TRPM4_channel_in_humans_causes_immune_dysregulation_with_defective_monocyte_migration/29715671CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/297156712024-09-04T06:00:00Z |
| spellingShingle | Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration Fang Yu (156838) Biological sciences Genetics Biomedical and clinical sciences Immunology TRPM4 immune dysregulation monocyte migration loss of function infections |
| status_str | publishedVersion |
| title | Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration |
| title_full | Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration |
| title_fullStr | Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration |
| title_full_unstemmed | Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration |
| title_short | Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration |
| title_sort | Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration |
| topic | Biological sciences Genetics Biomedical and clinical sciences Immunology TRPM4 immune dysregulation monocyte migration loss of function infections |