Ablation of Myeloid Cell MRP8 Ameliorates Nephrotoxic Serum-induced Glomerulonephritis by Affecting Macrophage Characterization through Intraglomerular Crosstalk
Ablation of Myeloid Cell MRP8 Ameliorates Nephrotoxic Serum-induced Glomerulonephritis by Affecting Macrophage Characterization through Intraglomerular Crosstalk
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DOI：
10.1038/s41598-020-59970-9
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发表时间：
2020-02-20
影响因子：
4.6
通讯作者：
Mukoyama, Masashi
中科院分区：
文献类型：
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作者：
Hata, Yusuke;Kuwabara, Takashige;Mukoyama, Masashi
toll样受体4 （TLR4）及其内源性配体之一髓系相关蛋白8 （MRP8或S100A8）在糖尿病肾病和自身免疫性疾病中发挥重要作用，尤其是在巨噬细胞中表达。然而，MRP8表达的详细机制和后果仍然未知，部分原因是MRP8敲除小鼠的胚胎致死性。在本研究中，产生髓系细胞特异性MRP8敲除小鼠，并发展肾毒性血清诱导的肾小球肾炎。与对照小鼠相比，骨髓细胞MRP8基因有条件消融的小鼠表现出较轻的组织学损伤、蛋白尿和炎症变化。通过培养细胞研究MRP8上调的机制。巨噬细胞与系膜细胞或系膜细胞条件培养基共培养，但不与近端小管共培养，巨噬细胞中MRP8基因表达和炎症M1表型显著上调，MRP8缺失的骨髓源性巨噬细胞中炎症M1表型减弱。在巨噬细胞诱导的c型凝集素（Mincle）的背景下，进一步研究了MRP8缺失的影响，该凝集素在巨噬细胞M1表型的维持中起关键作用。髓系细胞MRP8消融抑制了肾小球肾炎巨噬细胞中Mincle表达的诱导。因此，我们提出肾小球内系膜细胞和巨噬细胞之间的串扰在肾小球肾炎的炎症变化中起作用，巨噬细胞中mrp8依赖性Mincle的表达可能参与了这一过程。
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.