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

Abstract

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.

• Authors: Yusuke Hata, Takashige Kuwabara, Kiyoshi Mori, Youngna Kan, Yuki Sato, Shuro Umemoto, Daisuke Fujimoto, Tomoko Kanki, Yoshihiko Nishiguchi, Hideki Yokoi, Yutaka Kakizoe, Yuichiro Izumi, Motoko Yanagita, Masashi Mukoyama
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 3056 (02 20 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32080297 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Calgranulin A (deficiency, metabolism)
• Cell Lineage
• Disease Models, Animal
• Gene Deletion
• Glomerulonephritis (metabolism, pathology)
• Integrases (metabolism)
• Kidney Glomerulus (pathology)
• Lectins, C-Type (metabolism)
• Macrophages (metabolism, pathology)
• Membrane Proteins (metabolism)
• Mesangial Cells (metabolism)
• Mice
• Mice, Knockout
• Myeloid Progenitor Cells (metabolism)
• RAW 264.7 Cells
• Recombination, Genetic (genetics)
• Serum (metabolism)
• Stress Fibers (metabolism)
• Toll-Like Receptor 4 (metabolism)
• Up-Regulation