ADA2 regulates inflammation and hematopoietic stem cell emergence via the A2bR pathway in zebrafish

• DOI: 10.1038/s42003-024-06286-3
• Publication Date: 2024-05-22T10:01:25Z
• Authors: Alessia Brix; Laura Belleri; Alex Pezzotta; Emanuela Pettinato; Mara Mazzola; Matteo Zoccolillo; Anna Marozzi; Rui Monteiro; Filippo Del Bene; Alessandra Mortel...; Anna Pistocchi
• Keywords: Adenosine deaminase deficiency; Hematopoietic stem cell

Abstract Deficiency of adenosine deaminase 2 (DADA2) is an inborn error immunity caused by loss-of-function mutations in the ( ADA2 ) gene. Clinical manifestations DADA2 include vasculopathy and immuno-hematological abnormalities, culminating bone marrow failure. A major gap exists our knowledge regulatory functions during inflammation hematopoiesis, mainly due to absence orthologue rodents. Exploring these mechanisms essential for understanding disease pathology developing new treatments. Zebrafish possess two orthologues, cecr1a cecr1b , with latter showing functional conservation human ADA2. We establish a -loss-of-function zebrafish model that recapitulates vascular observed humans. Loss Cecr1b disrupts hematopoietic stem cell specification, resulting defective hematopoiesis. This defect induced endothelium. Blocking inflammation, pharmacological modulation r pathway, or administration recombinant corrects defects, providing insights into mechanistic link between deficiency, abnormalities. Our findings open up potential therapeutic avenues patients.