Cytidine deaminase enables Toll-like receptor 8 activation by cytidine or its analogs

Katsuhiro Furusho, Takuma Shibata, Ryota Sato, Ryutaro Fukui, Yuji Motoi, Yun Zhang, Shin Ichiroh Saitoh, Takeshi Ichinohe, Masafumi Moriyama, Seiji Nakamura, Kensuke Miyake

Research output: Contribution to journalArticle

Abstract

Toll-like receptor 8 (TLR8), a sensor for pathogen-derived single-stranded RNA (ssRNA), binds to uridine (Uri) and ssRNA to induce defense responses. We here show that cytidine (Cyd) with ssRNA also activated TLR8 in peripheral blood leukocytes (PBLs) and a myeloid cell line U937, but not in an embryonic kidney cell line 293T. Cyd deaminase (CDA), an enzyme highly expressed in leukocytes, deaminates Cyd to Uri. CDA expression enabled TLR8 response to Cyd and ssRNA in 293T cells. CDA deficiency and a CDA inhibitor both reduced TLR8 responses to Cyd and ssRNA in U937. The CDA inhibitor also reduced PBL response to Cyd and ssRNA. A Cyd analogue, azacytidine, is used for the therapy of myelodysplastic syndrome and acute myeloid leukemia. Azacytidine with ssRNA induced tumor necrosis factor-α expression in U937 and PBLs in a manner dependent on CDA and TLR8. These results suggest that CDA enables TLR8 activation by Cyd or its analogues with ssRNA through deaminating activity. Nucleoside metabolism might impact TLR8 responses in a variety of situations such as the treatment with nucleoside analogues.

Original languageEnglish
Pages (from-to)167-173
Number of pages7
JournalInternational immunology
Volume31
Issue number3
DOIs
Publication statusPublished - Mar 5 2019

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Furusho, K., Shibata, T., Sato, R., Fukui, R., Motoi, Y., Zhang, Y., ... Miyake, K. (2019). Cytidine deaminase enables Toll-like receptor 8 activation by cytidine or its analogs. International immunology, 31(3), 167-173. https://doi.org/10.1093/intimm/dxy075