Targeting erythroid cell-derived asparagine inhibits alloimmunization in sickle cell disease

Area of Science:

• Immunology
• Hematology
• Metabolomics

Background:

• Red blood cell (RBC) transfusions are vital for sickle cell disease (SCD) but risk alloimmunization.
• Metabolites, including amino acids, may influence immune responses in SCD.

Purpose of the Study:

• Investigate the role of L-asparagine (Asn) in RBC alloimmunization in SCD.
• Explore the potential of asparaginase (ASNase) as a therapeutic strategy.

Main Methods:

• Measured Asn levels in plasma and erythroid cells of SCD mice.
• Utilized reciprocal transfusion models and asparaginase treatment.
• Assessed B cell differentiation and Src family kinase (SFK) activation in vitro and in vivo.

Main Results:

• SCD mice exhibit increased plasma and erythroid Asn levels, linked to mitochondria-rich (Mito+) erythroid cells.
• ASNase treatment reduced RBC alloimmunization in SCD mice by inhibiting plasma cell differentiation.
• Asn supplementation promoted B cell differentiation, particularly in SCD patient cells, and ASNase reduced SFK activation.

Conclusions:

• The mitochondria-rich erythroid cell-Asn-SFK axis is implicated in RBC alloimmunization in SCD.
• Modulating Asn metabolism offers a potential therapeutic avenue for reducing alloimmunization in SCD.