A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Adenosine deaminase 2 regulates the activation of the toll-like receptor 9 in response to nucleic acids
Tekijät: Dong, Liang; Luo, Wenwen; Skaldin, Maksym; Robson, Simon C.; Zavialov, Andrey V.
Kustantaja: SPRINGER
Kustannuspaikka: NEW YORK
Julkaisuvuosi: 2024
Journal: Frontiers of Medicine
Tietokannassa oleva lehden nimi: FRONTIERS OF MEDICINE
Lehden akronyymi: FRONT MED-PRC
Vuosikerta: 18
Numero: 5
Aloitussivu: 814
Lopetussivu: 830
Sivujen määrä: 17
ISSN: 2095-0217
eISSN: 2095-0225
DOI: https://doi.org/10.1007/s11684-024-1067-5
Verkko-osoite: https://doi.org/10.1007/s11684-024-1067-5
Tiivistelmä
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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