Legumain, an asparaginyl endopeptidase, mediates the effect of M2 macrophages on attenuating renal interstitial fibrosis in obstructive nephropathy.
Legumain, an asparaginyl endopeptidase, mediates the effect of M2 macrophages on attenuating renal interstitial fibrosis in obstructive nephropathy.
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DOI：
10.1016/j.kint.2017.12.025
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发表时间：
2018-07
影响因子：
19.6
通讯作者：
Dekun Wang;M. Xiong;Chuanai Chen;Lingfang Du;Ze Liu;Yuzhi Shi;Mianzhi Zhang;Junbo Gong;Xiangrong Song;R. Xiang;Ergang Liu;Xiaoyue Tan
中科院分区：
文献类型：
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作者：
Dekun Wang;M. Xiong;Chuanai Chen;Lingfang Du;Ze Liu;Yuzhi Shi;Mianzhi Zhang;Junbo Gong;Xiangrong Song;R. Xiang;Ergang Liu;Xiaoyue Tan
在肾间质纤维化的发展过程中，两种不同的巨噬细胞表型参与了肾脏的损伤和修复；促炎症(M1)和抗炎(M2)巨噬细胞。Legumain是半胱氨酸蛋白酶家族中的一种天冬酰胺内肽酶，在某些病理条件下在巨噬细胞中过表达。然而，巨噬细胞来源的豆蛋白的巨噬细胞亚型和功能仍不清楚。为了解决这个问题，我们测试了M2巨噬细胞是否参与了单侧输尿管梗阻模型中豆类蛋白的积累。与野生型对照相比，豆类蛋白缺失的小鼠在梗阻后表现出更严重的纤维化病变。在体外，IL4刺激的M2极化导致豆类蛋白的过度表达和分泌。在转化生长因子-β-1刺激的肾小管上皮细胞或成纤维细胞的条件培养液中，经豆蛋白或IL-4刺激的巨噬细胞的条件培养液中，细胞外基质的主要成分纤维连接蛋白和I型/III型胶原的水平降低。给予豆类抑制剂RR-11a可加重梗阻后的纤维化损害。在治疗方面，过继转移高表达豆蛋白的巨噬细胞或IL4刺激的巨噬细胞可改善由输尿管梗阻引起的胶原和纤维连接蛋白沉积，无论是在野生型小鼠还是在IgMN-/-小鼠中。因此，M2巨噬细胞过度表达和分泌豆蛋白及豆蛋白介导了M2巨噬细胞在梗阻性肾病中的抗纤维化作用。
Two distinct macrophage phenotypes contribute to kidney injury and repair during the progression of renal interstitial fibrosis; proinflammatory (M1) and antiinflammatory (M2) macrophages. Legumain, an asparaginyl endopeptidase of the cysteine protease family, is overexpressed in macrophages in some pathological conditions. However, the macrophage subtype and function of macrophage-derived legumain remains unclear. To resolve this we tested whether M2 macrophages contribute to the accumulation of legumain in the unilateral ureteral obstruction model.Legumain-null mice exhibited more severe fibrotic lesions after obstruction compared with wild-type control.In vitro, IL4-stimulated M2 polarization led to the overexpression and secretion of legumain. The levels of fibronectin and collagen I/III, major components of the extracellular matrix, were reduced in the conditioned medium of TGF-β1-stimulated tubular epithelial cells or fibroblasts after treatment with legumain or conditioned medium from IL4-stimulated macrophages. Administration of the legumain inhibitor RR-11a exacerbated fibrotic lesions following obstruction. Therapeutically, adoptive transfer of legumain-overexpressing macrophages or IL4-stimulated macrophages ameliorated the deposition of collagen and fibronectin induced by ureteral obstruction, either in the wild-type mice or inlgmn–/–mice. Thus, M2 macrophages overexpress and secret legumain and legumain mediates the anti-fibrotic effect of M2 macrophages in obstructive nephropathy.