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TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6-mediated pathways in IgA nephropathy.
- Source :
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Kidney international [Kidney Int] 2020 Feb; Vol. 97 (2), pp. 340-349. Date of Electronic Publication: 2019 Sep 05. - Publication Year :
- 2020
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Abstract
- 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.<br /> (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1523-1755
- Volume :
- 97
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Kidney international
- Publication Type :
- Academic Journal
- Accession number :
- 31748116
- Full Text :
- https://doi.org/10.1016/j.kint.2019.08.022