Biliverdin Reductase A (BVRA) Mediates Macrophage Expression of Interleukin-10 in Injured Kidney.
Biliverdin Reductase A (BVRA) Mediates Macrophage Expression of Interleukin-10 in Injured Kidney.
复制标题
胆绿素还原酶 A (BVRA) 介导受损肾脏中巨噬细胞白细胞介素 10 的表达。
DOI：
10.3390/ijms160922621
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发表时间：
2015-09-18
影响因子：
5.6
通讯作者：
Xu G
中科院分区：
文献类型：
--
作者：
Hu Z;Pei G;Wang P;Yang J;Zhu F;Guo Y;Wang M;Yao Y;Zeng R;Liao W;Xu G
胆绿素还原酶A（Biliverdin Reductase A，BRA）是一种丝氨酸/苏氨酸/酪氨酸激酶激活的酶，在血红素降解途径中将胆绿素（BV）转化为胆红素（BR）。据报道，它在单核细胞和人胶质母细胞瘤中具有抗炎和抗氧化作用。然而，BVRA在极化巨噬细胞中的功能尚不清楚。本研究旨在探讨BVRA对损伤肾脏微环境中巨噬细胞活化和极化的影响。用GM-CSF和M-CSF诱导小鼠骨髓源性巨噬细胞的经典活化巨噬细胞（M1巨噬细胞）和交替活化巨噬细胞（M2巨噬细胞）极化。M1极化与BVRA和白细胞介素-10（IL-10）的显著下调以及TNF-α分泌的增加相关。我们还发现IL-10在BVRA过表达的巨噬细胞中表达增加，而在BVRA敲低的巨噬细胞中表达降低。相反，BVRA过表达或敲低巨噬细胞对TNF-α表达水平没有影响，表明BVRA介导巨噬细胞中IL-10的表达。此外，我们观察到，在巨噬细胞感染重组腺病毒BVRA基因，其中BVRA过表达增强INOS和ARG-1 mRNA的表达，导致一个特定的巨噬细胞表型。通过在体研究发现，BVRA阳性巨噬细胞大量存在于小鼠肾缺血再灌注损伤中。在损伤的肾脏微环境中分泌的常规细胞因子GM-CSF、M-CSF或LPS的处理下，BVRA过表达的巨噬细胞中IL-10的分泌显著增加。结论：BVRA阳性巨噬细胞是损伤肾脏中抗炎细胞因子IL-10的来源，这可能为肾脏疾病的治疗提供一个潜在的靶点。
Biliverdin reductase A is an enzyme, with serine/threonine/tyrosine kinase activation, converting biliverdin (BV) to bilirubin (BR) in heme degradation pathway. It has been reported to have anti-inflammatory and antioxidant effect in monocytes and human glioblastoma. However, the function of BVRA in polarized macrophage was unknown. This study aimed to investigate the effect of BVRA on macrophage activation and polarization in injured renal microenvironment. Classically activated macrophages (M1macrophages) and alternative activation of macrophages (M2 macrophages) polarization of murine bone marrow derived macrophage was induced by GM-CSF and M-CSF. M1 polarization was associated with a significant down-regulation of BVRA and Interleukin-10 (IL-10), and increased secretion of TNF-α. We also found IL-10 expression was increased in BVRA over-expressed macrophages, while it decreased in BVRA knockdown macrophages. In contrast, BVRA over-expressed or knockdown macrophages had no effect on TNF-α expression level, indicating BVRA mediated IL-10 expression in macrophages. Furthermore, we observed in macrophages infected with recombinant adenoviruses BVRA gene, which BVRA over-expressed enhanced both INOS and ARG-1 mRNA expression, resulting in a specific macrophage phenotype. Through in vivo study, we found BVRA positive macrophages largely existed in mice renal ischemia perfusion injury. With the treatment of the regular cytokines GM-CSF, M-CSF or LPS, excreted in the injured renal microenvironment, IL-10 secretion was significantly increased in BVRA over-expressed macrophages. In conclusion, the BVRA positive macrophage is a source of anti-inflammatory cytokine IL-10 in injured kidney, which may provide a potential target for treatment of kidney disease.