Developmental beta-cell death orchestrates the islet's inflammatory milieu by regulating immune system crosstalk

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

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.

Details

OriginalspracheEnglisch
Aufsatznummerbtad674
Seiten (von - bis)1131-1153
Seitenumfang23
FachzeitschriftThe EMBO journal
Jahrgang44
Ausgabenummer4
Frühes Online-Datum6 Jan. 2025
PublikationsstatusVeröffentlicht - Feb. 2025
Peer-Review-StatusJa

Externe IDs

ORCID /0000-0003-0137-5106/work/175217733
ORCID /0000-0003-4306-930X/work/175219604
Scopus 85214209472

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Bibliotheksschlagworte