Abstract: TH-PO041
TLR9 Activation Induces Overproduction of Aberrantly Glycosylated IgA through the APRIL Mediated Pathway in IgA Nephropathy
Session Information
- Glomerular: Basic/Experimental Immunology and Inflammation - I
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Glomerular
- 1001 Glomerular: Basic/Experimental Immunology and Inflammation
Authors
- Makita, Yuko, Juntendo University Faculty of Medicine, Tokyo, Japan
- Suzuki, Hitoshi, Juntendo University Faculty of Medicine, Tokyo, Japan
- Nihei, Yoshihito, Juntendo University Faculty of Medicine, Tokyo, Japan
- Julian, Bruce A., University of Alabama at Birmingham, Birmingham, Alabama, United States
- Novak, Jan, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Suzuki, Yusuke, Juntendo University Faculty of Medicine, Tokyo, Japan
Background
Involvement of Toll-like receptor 9 (TLR9) that play a key role in the innate immune system has been discussed in the pathogenesis of IgA nephropathy (IgAN). There are increasing evidences that galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1 containing immune complexes (ICs) have critical roles in the pathogenesis of IgAN. We recently demonstrated that interleukin-6 (IL-6) can enhance the production of Gd-IgA1 by IgA1-producing cells. Moreover, A proliferation-inducing ligand (APRIL) may be involved in the overproduction of the nephritogenic IgA1. However, the mechanisms leading to overproduction of Gd-IgA1 and subsequent formation of Gd-IgA1 containing ICs are still unclear.
Methods
IgAN prone ddY mice were divided into two groups with CpG-ODN (TLR9 ligand) immunization (n=19) or without (n=19). CpG-ODN was injected intraperitoneally 3 times a week for 12 weeks. Renal pathology and serum levels of aberrantly glycosylated IgA (Gd-IgA), IgG-IgA ICs, IL-6 and APRIL were evaluated after 12 weeks. We also examined the mechanisms of production of Gd-IgA1 in human IgA1-secreting cells through TLR9 activation and stimulation with IL-6 and APRIL.
Results
Mice immunized with CpG-ODN, but not non-immunized mice, showed mesangioproliferative glomerulonephritis accompanied by mesangial deposition of IgA, and C3. Immunization with CpG-ODN elevated serum levels of Gd-IgA, IgG-IgA IC and APRIL (P<0.05). Serum levels of APRIL significantly correlated with serum level of Gd-IgA and IgG-IgA IC (P<0.05). The activation of TLR9 induced production of IL-6, and IL-6 stimulation induced overexpression of APRIL in splenocytes. Moreover, in human IgA1-secreting cells, TLR9 activation enhanced Gd-IgA1 production through overexpressions of IL-6 and APRIL. Production of Gd-IgA1 was reduced by anti-IL-6 and/or siRNA for APRIL. However, anti-IL-6 could not inhibit overproduction of APRIL completely.
Conclusion
TLR9 activation exacerbated murine IgAN by enhancing production of aberrantly glycosylated IgA and nephritogenic ICs. TLR9 activation induced overproduction of IL-6 and APRIL. Present study suggested that TLR9-induced overproduction of both IL-6 and APRIL resulted in enhancing production of Gd-IgA1 and subsequent formation of Gd-IgA1 containing ICs in IgAN.
Funding
- Government Support - Non-U.S.