PUBLICATION
Developmental beta-cell death orchestrates the islet's inflammatory milieu by regulating immune system crosstalk
- Authors
- Akhtar, M.N., Hnatiuk, A., Delgadillo-Silva, L., Geravandi, S., Sameith, K., Reinhardt, S., Bernhardt, K., Singh, S.P., Maedler, K., Brusch, L., Ninov, N.
- ID
- ZDB-PUB-250109-170
- Date
- 2025
- Source
- The EMBO journal : (Journal)
- Registered Authors
- Akhtar, Nadeem, Ninov, Nikolay, Singh, Sumeet Pal
- Keywords
- Dedifferentiationp, Excitotoxicity, Macrophage, T Regulatory Cell, Type 1 Diabetes
- Datasets
- GEO:GSE261729
- MeSH Terms
-
- Inflammation/immunology
- Inflammation/metabolism
- Inflammation/pathology
- Animals
- Apoptosis*
- Islets of Langerhans/immunology
- Islets of Langerhans/metabolism
- Islets of Langerhans/pathology
- Macrophages/immunology
- Macrophages/metabolism
- Cell Death
- Zebrafish*/immunology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Insulin-Secreting Cells*/immunology
- Insulin-Secreting Cells*/metabolism
- Insulin-Secreting Cells*/pathology
- Signal Transduction
- NF-kappa B/metabolism
- PubMed
- 39762647 Full text @ EMBO J.
Citation
Akhtar, M.N., Hnatiuk, A., Delgadillo-Silva, L., Geravandi, S., Sameith, K., Reinhardt, S., Bernhardt, K., Singh, S.P., Maedler, K., Brusch, L., Ninov, N. (2025) Developmental beta-cell death orchestrates the islet's inflammatory milieu by regulating immune system crosstalk. The EMBO journal. :.
Abstract
While pancreatic beta-cell proliferation has been extensively studied, the role of cell death during islet development remains incompletely understood. Using a genetic model of caspase inhibition in beta cells coupled with mathematical modeling, we here discover an onset of beta-cell death in juvenile zebrafish, which regulates beta-cell mass. Histologically, this beta-cell death is underestimated due to phagocytosis by resident macrophages. To investigate beta-cell apoptosis at the molecular level, we implement a conditional model of beta-cell death linked to Ca2+ overload. Transcriptomic analysis reveals that metabolically-stressed beta cells follow paths to either de-differentiation or apoptosis. Beta cells destined to die activate inflammatory and immuno-regulatory pathways, suggesting that cell death regulates the crosstalk with immune cells. Consistently, inhibiting beta-cell death during development reduces pro-inflammatory resident macrophages and expands T-regulatory cells, the deficiency of which causes premature activation of NF-kB signaling in beta cells. Thus, developmental cell death not only shapes beta-cell mass but it also influences the islet's inflammatory milieu by shifting the immune-cell population towards pro-inflammatory.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping