Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration - 05/09/24
, Amel Hassan, MD k, ⁎ , Khaled Machaca, PhD a, b, ⁎ Abstract |
Background |
TRPM4 is a broadly expressed, calcium-activated, monovalent cation channel that regulates immune cell function in mice and cell lines. Clinically, however, partial loss- or gain-of-function mutations in TRPM4 lead to arrhythmia and heart disease, with no documentation of immunologic disorders.
Objective |
To characterize functional cellular mechanisms underlying the immune dysregulation phenotype in a proband with a mutated TRPM4 gene.
Methods |
We employed a combination of biochemical, cell biological, imaging, omics analyses, flow cytometry, and gene editing approaches.
Results |
We report the first human cases to our knowledge with complete loss of the TRPM4 channel, leading to immune dysregulation with frequent bacterial and fungal infections. Single-cell and bulk RNA sequencing point to altered expression of genes affecting cell migration, specifically in monocytes. Inhibition of TRPM4 in T cells and the THP-1 monocyte cell line reduces migration. More importantly, primary T cells and monocytes from TRPM4 patients migrate poorly. Finally, CRISPR knockout of TRPM4 in THP-1 cells greatly reduces their migration potential.
Conclusion |
Our results demonstrate that TRPM4 plays a critical role in regulating immune cell migration, leading to increased susceptibility to infections.
Le texte complet de cet article est disponible en PDF.Key words : TRPM4, immune dysregulation, monocyte, migration, loss of function, infections
Abbreviations used : APC, CBA, DEG, GFP, GI, gRNA, IRB, NC, NMDG, 9-Phe, RNA-Seq, SOCE, TG
Plan
Vol 154 - N° 3
P. 792-806 - septembre 2024 Retour au numéro
Article précédent
- The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans
- Carole Le Coz, Melissa Trofa, Dorothy L. Butler, Samuel Yoon, Tian Tian, Whitney Reid, Emylette Cruz Cabrera, Ainsley V.C. Knox, Caroline Khanna, Kathleen E. Sullivan, Jennifer Heimall, Patricia Takach, Olajumoke O. Fadugba, Monica Lawrence, Soma Jyonouchi, Hakon Hakonarson, Andrew D. Wells, Steven Handler, Karen B. Zur, Vinodh Pillai, Jeffrey C. Gildersleeve, Neil Romberg
- Whole blood transcriptome in long-COVID patients reveals association with lung function and immune response
- Jelle M. Blankestijn, Nadia Baalbaki, Somayeh Bazdar, Inés Beekers, Rosanne J.H.C.G. Beijers, Joop P. van den Bergh, Lizan D. Bloemsma, Merel E.B. Cornelissen, Tamara Dekker, Jan Willem Duitman, Laura Houweling, John J.L. Jacobs, Ivo van der Lee, Paulien M.A. Linders, Lieke C.E. Noij, Esther J. Nossent, Marianne A. van de Pol, Brigitte M. Sondermeijer, J.J. Miranda Geelhoed, Els J.M. Weersink, Korneliusz Golebski, Mahmoud I. Abdel-Aziz, Anke H. Maitland-van der Zee, P4O2 Consortium
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?