Adenosine deaminase 2 regulates the activation of the toll-like receptor 9 in response to nucleic acids

Abstract

Human cells contain two types of adenosine deaminases (ADA) each with unique properties: ADA1, which is present in all cells where it modulates intracellular functions and extracellular signaling, and ADA2, which is secreted by immune cells. The exact intracellular functions of ADA2 remain undetermined and less defined than those of ADA1. ADA2 has distinct characteristics, such as low adenosine affinity, heparin-binding ability, and putative lysosomal entry. Here, we confirm that ADA2 is a lysosomal protein that binds toll-like receptor 9 (TLR9) agonists, specifically CpG oligodeoxynucleotides (CpG ODNs). We show that interferon-alpha (IFN-α) is secreted in response to TLR9 activation by CpG ODNs and natural DNA and markedly increases when ADA2 expression is downregulated in plasmacytoid dendritic cells (pDCs). Additionally, the pretreatment of pDCs with RNA further stimulates IFN-α secretion by pDCs after activation with CpG ODNs. Our findings indicate that ADA2 regulates TLR9 responses to DNA in activated pDCs. In conclusion, decreasing ADA2 expression or blocking it with specific oligonucleotides can enhance IFN-α secretion from pDCs, improving immune responses against intracellular infections and cancer.

Keywords

adenosine deaminase 2 / plasmacytoid dendritic cell / TLR9 / IL-3 / IFN-α / CpG ODN

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Acknowledgments

The authors wish to thank the staff of the Institute of Pediatrics for participating in the study.

Compliance with ethics guidelines

The authors declare that the research was conducted without commercial or financial relationships that can be considered a conflict of interest. Simon C. Robson is a scientific founder of Purinomia Biotech Inc. and consults for eGenesis, AbbVie, and SynLogic Inc.; his interests are reviewed and managed by HMFP at Beth Israel Deaconess Medical Center in accordance with the conflict-of-interest policies.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1067-5 and is accessible to authorized users.

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