Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration.
J Allergy Clin Immunol
; 154(3): 792-806, 2024 Sep.
Article
in En
| MEDLINE
| ID: mdl-38750824
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Monocytes
/
Cell Movement
/
TRPM Cation Channels
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
J Allergy Clin Immunol
/
J. allergy clin. immunol
/
Journal of allergy and clinical immunology
Year:
2024
Type:
Article