PUBLICATION
ADA2 regulates inflammation and hematopoietic stem cell emergence via the A2bR pathway in zebrafish
- Authors
- Brix, A., Belleri, L., Pezzotta, A., Pettinato, E., Mazzola, M., Zoccolillo, M., Marozzi, A., Monteiro, R., Del Bene, F., Mortellaro, A., Pistocchi, A.
- ID
- ZDB-PUB-240523-11
- Date
- 2024
- Source
- Communications biology 7: 615615 (Journal)
- Registered Authors
- Del Bene, Filippo, Monteiro, Rui
- Keywords
- none
- MeSH Terms
-
- Adenosine Deaminase*/deficiency
- Adenosine Deaminase*/genetics
- Adenosine Deaminase*/metabolism
- Animals
- Hematopoiesis*/genetics
- Hematopoietic Stem Cells*/metabolism
- Humans
- Inflammation*/genetics
- Inflammation*/metabolism
- Intercellular Signaling Peptides and Proteins/genetics
- Intercellular Signaling Peptides and Proteins/metabolism
- Signal Transduction
- Zebrafish*/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 38777862 Full text @ Commun Biol
Citation
Brix, A., Belleri, L., Pezzotta, A., Pettinato, E., Mazzola, M., Zoccolillo, M., Marozzi, A., Monteiro, R., Del Bene, F., Mortellaro, A., Pistocchi, A. (2024) ADA2 regulates inflammation and hematopoietic stem cell emergence via the A2bR pathway in zebrafish. Communications biology. 7:615615.
Abstract
Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity caused by loss-of-function mutations in the adenosine deaminase 2 (ADA2) gene. Clinical manifestations of DADA2 include vasculopathy and immuno-hematological abnormalities, culminating in bone marrow failure. A major gap exists in our knowledge of the regulatory functions of ADA2 during inflammation and hematopoiesis, mainly due to the absence of an ADA2 orthologue in rodents. Exploring these mechanisms is essential for understanding disease pathology and developing new treatments. Zebrafish possess two ADA2 orthologues, cecr1a and cecr1b, with the latter showing functional conservation with human ADA2. We establish a cecr1b-loss-of-function zebrafish model that recapitulates the immuno-hematological and vascular manifestations observed in humans. Loss of Cecr1b disrupts hematopoietic stem cell specification, resulting in defective hematopoiesis. This defect is caused by induced inflammation in the vascular endothelium. Blocking inflammation, pharmacological modulation of the A2r pathway, or the administration of the recombinant human ADA2 corrects these defects, providing insights into the mechanistic link between ADA2 deficiency, inflammation and immuno-hematological abnormalities. Our findings open up potential therapeutic avenues for DADA2 patients.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping