Abstract: TH-PO546
Nucleotide-Sensing TLR9/TLR7 System Is a Potential Therapeutic Target for IgA Nephropathy
Session Information
- Glomerular Diseases: From Inflammation to Fibrosis - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: From Inflammation to Fibrosis
Authors
- Lee, Mingfeng, Juntendo University Faculty of Medicine, Tokyo, Japan
- Suzuki, Hitoshi, Juntendo University Faculty of Medicine, Tokyo, Japan
- Aoki, Ryousuke, Juntendo University Faculty of Medicine, Tokyo, Japan
- Kato, Rina, Juntendo University Faculty of Medicine, Tokyo, Japan
- Fukao, Yusuke, Juntendo University Faculty of Medicine, Tokyo, Japan
- Nakayama, Maiko, Juntendo University Faculty of Medicine, Tokyo, Japan
- Nihei, Yoshihito, Juntendo University Faculty of Medicine, Tokyo, Japan
- Kano, Toshiki, Juntendo University Faculty of Medicine, Tokyo, Japan
- Makita, Yuko, Juntendo University Faculty of Medicine, Tokyo, Japan
- Suzuki, Yusuke, Juntendo University Faculty of Medicine, Tokyo, Japan
Background
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Galactose-deficient IgA1 (Gd-IgA1) is a key effector molecule in the pathogenesis of IgAN. Previous reports indicated that toll-like receptor (TLR)9 and TLR7 are involved in synthesizing Gd-IgA1. TLR9 and TLR7 recognize microbial DNA and RNA, respectively. Several clinical trials suggested hydroxychloroquine (HCQ), known to suppress TLR9/TLR7, might effectively treat IgAN. The present study aimed to clarify whether TLR9/TLR7 could be the therapeutic targets for IgAN.
Methods
First, we divided the ddY mice, the spontaneous IgAN model, into the control group, HCQ administered group, CpG-ODN (ligand of TLR9) nasally administered group, CpG-ODN + HCQ group, Imiquimod (ligand of TLR7) nasally administered group, and Imiquimod + HCQ group, respectively. We analyzed the serum aberrantly-glycosylated IgA, IgG-IgA immune complexes (IC), proteinuria, and renal pathology. Next, we cultured the splenocytes of ddY mice with CpG-ODN or Imiquimod. We analyzed the effect on the synthesis of aberrantly-glycosylated IgA. Finally, we cultured tonsillar mononuclear cells (TMCs) from IgAN patients with CpG-ODN or Imiquimod. We analyzed the cellular expression of C1GaLT1, an enzyme involved in IgA1 glycosylation, and the supernatant Gd-IgA1 levels.
Results
The mice administered with CpG-ODN or Imiquimod showed elevated serum levels of aberrantly-glycosylated IgA and IgG-IgA IC. Furthermore, these mice showed aggravated proteinuria. Renal pathological findings further confirmed glomerular mesangial proliferation accompanied by significant IgA/IgG/C3 depositions. The mice co-administered with HCQ did not show the changes that CpG-ODN or Imiquimod induced. The splenocytes of ddY mice significantly elevated IL-6, known to affect IgA glycosylation, and promoted aberrantly-glycosylated IgA when stimulated by CpG-ODN or Imiquimod. In the human studies, stimulation with CpG-ODN or Imiquimod let the cultured TMCs promote IL-6 synthesis, downregulated C1GaLT1 and consequently enhanced the production of Gd-IgA1.
Conclusion
Present data suggested that nucleotide-sensing TLR9/TLR7 are involved in the pathogenesis of IgAN and might be the candidates for disease-specific therapeutic targets.