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

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 a conserved function with human ADA2. We established a new cecr1b-loss-of-function zebrafish model that recapitulates the immuno-hematological and vascular manifestations observed in humans. DADA2 phenotypes could be corrected by administrating recombinant human ADA2. Cecr1b deficiency disrupts the hematopoietic stem cells specification, resulting in defective hematopoiesis. This defect is accompanied by spontaneous inflammation. Pharmacological modulation of the A2br pathway corrects these defects, providing insights into the mechanistic link between ADA2 deficiency and immuno-hematological abnormalities. Moreover, our findings open up novel therapeutic avenues for DADA2 patients.