Ablation of Myeloid Cell MRP8 Ameliorates Nephrotoxic Serum-induced Glomerulonephritis by Affecting Macrophage Characterization through Intraglomerular Crosstalk.


Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
20 02 2020
Historique:
received: 27 11 2019
accepted: 03 02 2020
entrez: 22 2 2020
pubmed: 23 2 2020
medline: 13 11 2020
Statut: epublish

Résumé

Toll-like receptor 4 (TLR4) and one of its endogenous ligands myeloid-related protein 8 (MRP8 or S100A8), especially expressed in macrophages, play an important role in diabetic nephropathy and autoimmune disorders. However, detailed mechanisms and consequence of MRP8 expression remain unknown, partly due to embryonic lethality of MRP8 knockout mice. In this study, Myeloid lineage cell-specific MRP8 knockout mice were generated, and nephrotoxic serum-induced glomerulonephritis was developed. Mice with conditional ablation of MRP8 gene in myeloid cells exhibited less severe histological damage, proteinuria and inflammatory changes compared to control mice. Mechanism of MRP8 upregulation was investigated using cultured cells. Co-culture of macrophages with mesangial cells or mesangial cell-conditioned media, but not with proximal tubules, markedly upregulated MRP8 gene expression and inflammatory M1 phenotype in macrophages, which was attenuated in MRP8-deleted bone marrow-derived macrophages. Effects of MRP8 deletion was further studied in the context of macrophage-inducible C-type lectin (Mincle), which is critically involved in maintenance of M1 phenotype of macrophages. MRP8 ablation in myeloid cells suppressed the induction of Mincle expression on macrophages in glomerulonephritis. Thus, we propose that intraglomerular crosstalk between mesangial cells and macrophages plays a role in inflammatory changes in glomerulonephritis, and MRP8-dependent Mincle expression in macrophage may be involved in the process.

Identifiants

pubmed: 32080297
doi: 10.1038/s41598-020-59970-9
pii: 10.1038/s41598-020-59970-9
pmc: PMC7033179
doi:

Substances chimiques

Calgranulin A 0
Clecsf8 protein, mouse 0
Lectins, C-Type 0
Membrane Proteins 0
S100a8 protein, mouse 0
Toll-Like Receptor 4 0
Cre recombinase EC 2.7.7.-
Integrases EC 2.7.7.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3056

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Auteurs

Yusuke Hata (Y)

Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Takashige Kuwabara (T)

Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan. ktakasea@kumamoto-u.ac.jp.
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan. ktakasea@kumamoto-u.ac.jp.

Kiyoshi Mori (K)

Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Nephrology and Kidney Research, Shizuoka General Hospital, Shizuoka, Japan.
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

Youngna Kan (Y)

Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Yuki Sato (Y)

Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Shuro Umemoto (S)

Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Daisuke Fujimoto (D)

Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Tomoko Kanki (T)

Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Yoshihiko Nishiguchi (Y)

Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Hideki Yokoi (H)

Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Yutaka Kakizoe (Y)

Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Yuichiro Izumi (Y)

Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Motoko Yanagita (M)

Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan.

Masashi Mukoyama (M)

Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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Classifications MeSH