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The nucleotide-sensing Toll-Like Receptor 9/Toll-Like Receptor 7 system is a potential therapeutic target for IgA nephropathy.
Lee, Mingfeng; Suzuki, Hitoshi; Ogiwara, Kei; Aoki, Ryosuke; Kato, Rina; Nakayama, Maiko; Fukao, Yusuke; Nihei, Yoshihito; Kano, Toshiki; Makita, Yuko; Muto, Masahiro; Yamada, Koshi; Suzuki, Yusuke.
Afiliación
  • Lee M; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Suzuki H; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan; Department of Nephrology, Juntendo University Urayasu Hospital, Chiba, Japan. Electronic address: shitoshi@juntendo.ac.jp.
  • Ogiwara K; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Aoki R; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Kato R; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Nakayama M; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Fukao Y; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Nihei Y; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Kano T; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Makita Y; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Muto M; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Yamada K; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Suzuki Y; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan. Electronic address: yusuke@juntendo.ac.jp.
Kidney Int ; 104(5): 943-955, 2023 Nov.
Article en En | MEDLINE | ID: mdl-37648155
The progression determinants of IgA nephropathy (IgAN) are still not fully elucidated. We have previously demonstrated that the mucosal activation of toll-like receptor (TLR) 9, which senses microbial unmethylated CpG DNA, influences progression by producing aberrantly glycosylated IgA. However, numerous recent reports of patients with IgAN presenting with gross hematuria after the mRNA vaccination for coronavirus disease 2019 suggest that the RNA-sensing system also exacerbates IgAN. Here, we investigated whether TLR7, which recognizes microbial RNA, is also involved in IgAN progression using a murine model and tonsil tissue from 53 patients with IgAN compared to samples from 40 patients with chronic tonsillitis and 12 patients with sleep apnea syndrome as controls. We nasally administered imiquimod, the ligand of TLR7, to IgAN-prone ddY mice and found that TLR7 stimulation elevated the serum levels of aberrantly glycosylated IgA and induced glomerular IgA depositions and proteinuria. Co-administered hydroxychloroquine, which inhibits TLRs, canceled the kidney injuries. In vitro, stimulating splenocytes from ddY mice with imiquimod increased interleukin-6 and aberrantly glycosylated IgA levels. The expression of TLR7 in the tonsils was elevated in patients with IgAN and positively correlated with that of a proliferation-inducing ligand (APRIL) involved in the production of aberrantly glycosylated IgA. Mechanistically, TLR7 stimulation enhanced the synthesis of aberrantly glycosylated IgA through the modulation of enzymes involved in the glycosylation of IgA. Thus, our findings suggest that nucleotide-sensing TLR9 and TLR7 play a crucial role in the pathogenesis of IgAN. Hence, nucleotide-sensing TLRs could be reasonably strong candidates for disease-specific therapeutic targets in IgAN.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Kidney Int Año: 2023 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Kidney Int Año: 2023 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos