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

Alessia Brix, Laura Belleri, Alex Pezzotta, Emanuela Pettinato, Mara Mazzola, Matteo Zoccolillo, Anna Marozzi, Rui Monteiro, Filippo Del Bene, Alessandra Mortellaro*, Anna Pistocchi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.
Original languageEnglish
Article number615
Number of pages14
JournalCommunications Biology
Volume7
Issue number1
Early online date22 May 2024
DOIs
Publication statusPublished - Dec 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry,Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

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