A1 Refereed original research article in a scientific journal
Adenosine deaminase 2 regulates the activation of the toll-like receptor 9 in response to nucleic acids
Authors: Dong, Liang; Luo, Wenwen; Skaldin, Maksym; Robson, Simon C.; Zavialov, Andrey V.
Publisher: SPRINGER
Publishing place: NEW YORK
Publication year: 2024
Journal: Frontiers of Medicine
Journal name in source: FRONTIERS OF MEDICINE
Journal acronym: FRONT MED-PRC
Volume: 18
Issue: 5
First page : 814
Last page: 830
Number of pages: 17
ISSN: 2095-0217
eISSN: 2095-0225
DOI: https://doi.org/10.1007/s11684-024-1067-5
Web address : https://doi.org/10.1007/s11684-024-1067-5
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-alpha) 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-alpha 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-alpha secretion from pDCs, improving immune responses against intracellular infections and cancer.
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-alpha) 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-alpha 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-alpha secretion from pDCs, improving immune responses against intracellular infections and cancer.
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