The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation
The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation
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模式识别受体 Mincle 对于维持急性肾脏炎症中的 M1 巨噬细胞表型至关重要
DOI：
10.1016/j.kint.2016.10.020
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发表时间：
2017-03-01
影响因子：
19.6
通讯作者：
Lan, Hui-Yao
中科院分区：
文献类型：
--
作者：
Lv, Lin L.;Tang, Patrick Ming-Kuen;Lan, Hui-Yao
Mincle（macrophage-inducible C-type lectin，Clec 4 e）是一种参与先天免疫的跨膜模式识别受体，但其在肾脏疾病中的作用尚不清楚。在肾损伤单侧输尿管梗阻模型的梗阻肾中，第1天在浸润的M1巨噬细胞（CD 68（+）iNOS（+）细胞）中特异性检测到Mincle，但在肾损伤进展期间随着M1巨噬细胞减少而迅速减少。有趣的是，在顺铂诱导的急性肾损伤模型中，表达Mincle的巨噬细胞进行性增加，其中在Mincle诱导后的CD 68（+）细胞中检测到iNOS表达。Mincle（+）M1巨噬细胞的适应性转移在很大程度上促进了顺铂诱导的肾脏炎症，这通过在转移的细胞中敲低Mincle来防止。明克尔受到严格的监管。LPS引发的巨噬细胞中NF-κ B/p65与Mincle启动子区的结合证明了TLR 4/NF-κ B信号传导。阻断TLR 4或NF-κ B可抑制LPS诱导的巨噬细胞Mincle表达。重要的是，发现Mincle对于通过Syk信号传导途径维持M1巨噬细胞的炎性表型是必不可少的，因为Mincle的敲低或Syk的抑制抑制LPS诱导的IL-1 β、MCP-1和iNOS表达。因此，Mincle在M1巨噬细胞上特异性诱导，其中Mincle-Syk信号传导促进并维持急性肾脏炎症中M1巨噬细胞的炎性表型。因此，靶向Mincle可能是与M1巨噬细胞相关的急性肾损伤的新疗法。
Mincle (macrophage-inducible C-type lectin, Clec4e) is a transmembrane pattern recognition receptor involving the innate immunity, but its role in kidney disease is still unexplored. In the obstructed kidney of the unilateral ureteral obstruction model of renal injury, Mincle was specifically detected in the infiltrating M1 macrophages (CD68(+)iNOS(+) cells) on day one but was rapidly reduced following reduction of M1 macrophages during the progression of kidney injury. Interestingly, Mincle-expressing macrophages were progressively increased in the cisplatin-induced acute kidney injury model, where iNOS expression was detected in the CD68(+) cells following Mincle induction. Adaptive transfer of Mincle(+) M1 macrophages largely promoted cisplatin-induced renal inflammation, which was prevented by the knockdown of Mincle in the transferred cells. Mincle was tightly regulated by. TLR4/NF-kappa B signaling as evidenced by the binding of NF-kappa B/p65 to the promoter region of Mincle in LPS-primed macrophages. Blocking TLR4 or NF-kappa B suppressed LPS-induced Mincle expression on macrophages. Importantly, Mincle was found to be essential for maintaining the inflammatory phenotypes of M1 macrophages through the Syk signaling pathway since knockdown of Mincle or inhibition of Syk suppressed LPS-induced IL-1 beta, MCP-1, and iNOS expression. Thus, Mincle is induced specifically on M1 macrophages, where Mincle-Syk signaling promotes and maintains inflammatory phenotypes of M1 macrophages in acute renal inflammation. Hence, targeting Mincle may be a novel therapy for acute kidney injury associated with M1 macrophages.