Adenosine deaminase 2 regulates the activation of the toll-like receptor 9 in response to nucleic acids
Liang Dong2,3, Wenwen Luo2, Skaldin Maksym2,4, Simon C. Robson5, Andrey V. Zavialov1,2()
. International Center for Aging and Cancer (ICAC), Hainan Medical University, Haikou 571199, China . Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China . Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China . Joint Biotechnology Laboratory, University of Turku, Turku 20520, Finland . Center for Inflammation Research, Departments of Anesthesia and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston 02215, USA
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.
. [J]. Frontiers of Medicine, 2024, 18(5): 814-830.
Liang Dong, Wenwen Luo, Skaldin Maksym, Simon C. Robson, Andrey V. Zavialov. Adenosine deaminase 2 regulates the activation of the toll-like receptor 9 in response to nucleic acids. Front. Med., 2024, 18(5): 814-830.
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