TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6-mediated pathways in IgA nephropathy

• Published in: Kidney international Vol. 97; no. 2; p. 340
• Main Authors: Makita, Yuko, Suzuki, Hitoshi, Kano, Toshiki, Takahata, Akiko, Julian, Bruce A, Novak, Jan, Suzuki, Yusuke
• Format: Journal Article
• Language: English
• Published: United States 01-02-2020
• Subjects: Animals; Galactose; Glomerulonephritis, IGA; Glycosylation; Immunoglobulin A - metabolism; Interleukin-6; Ligands; Mice; Toll-Like Receptor 9 - genetics; Tumor Necrosis Factor Ligand Superfamily Member 13; galactose-deficient IgA1; IgA nephropathy; immune complex; IL-6; APRIL
• ISSN: 1523-1755
• DOI: 10.1016/j.kint.2019.08.022

Galactose-deficient IgA1 (Gd-IgA1) plays a crucial role in the development of IgA nephropathy (IgAN). However, the pathogenic mechanisms driving Gd-IgA1 production have not been fully elucidated. Innate-immune activation via Toll-like receptor 9 (TLR9) is known to be involved in Gd-IgA1 production. A proliferation inducing ligand (APRIL) and IL-6 are also known to enhance Gd-IgA1 synthesis in IgAN. With this as background, we investigated how TLR9 activation in IgA secreting cells results in overproduction of nephritogenic IgA in the IgAN-prone ddY mouse and in human IgA1-secreting cells. Injection of the TLR9 ligand CpG-oligonucleotides increased production of aberrantly glycosylated IgA and IgG-IgA immune complexes in ddY mice that, in turn, exacerbated kidney injury. CpG-oligonucleotide-stimulated mice had elevated serum levels of APRIL that correlated with those of aberrantly glycosylated IgA and IgG-IgA immune complexes. In vitro, TLR9 activation enhanced production of the nephritogenic IgA as well as APRIL and IL-6 in splenocytes of ddY mice and in human IgA1-secreting cells. However, siRNA knock-down of APRIL completely suppressed overproduction of Gd-IgA1 induced by IL-6. Neutralization of IL-6 decreased CpG-oligonucleotide-induced overproduction of Gd-IgA1. Furthermore, APRIL and IL-6 pathways each independently mediated TLR9-induced overproduction of Gd-IgA1. Thus, TLR9 activation enhanced synthesis of aberrantly glycosylated IgA that, in a mouse model of IgAN, further enhanced kidney injury. Hence, APRIL and IL-6 synergistically, as well as independently, enhance synthesis of Gd-IgA1.