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
em 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Monócitos
/
Movimento Celular
/
Canais de Cátion TRPM
Limite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Allergy Clin Immunol
Ano de publicação:
2024
Tipo de documento:
Article