Notch Signaling Modulates Macrophage Polarization and Phagocytosis Through Direct Suppression of Signal Regulatory Protein α Expression.
Notch Signaling Modulates Macrophage Polarization and Phagocytosis Through Direct Suppression of Signal Regulatory Protein α Expression.
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Notch 信号传导通过直接抑制信号调节蛋白 α 表达来调节巨噬细胞极化和吞噬作用
DOI：
10.3389/fimmu.2018.01744
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发表时间：
2018
影响因子：
7.3
通讯作者：
Han H
中科院分区：
文献类型：
--
作者：
Lin Y;Zhao JL;Zheng QJ;Jiang X;Tian J;Liang SQ;Guo HW;Qin HY;Liang YM;Han H
Notch信号通路在骨髓细胞的发育和功能调节中起着关键作用。先前的研究表明，Notch激活促进M1极化和巨噬细胞的吞噬作用;然而，介导Notch信号的下游分子机制仍然难以捉摸。为了利用质谱鉴定骨髓源性巨噬细胞（BMDM）中Notch下游靶点，信号调节蛋白α（SIRPα）似乎响应于敲除巨噬细胞中Notch通路的关键转录因子重组信号结合蛋白Jk（RBP-J）。在这项研究中，我们验证了Notch激活可能通过Hes家族辅阻遏物抑制SIRPα表达。SIRPα促进巨噬细胞M2极化，这依赖于与CD 47的相互作用，并通过SHP-1介导的细胞内信号传导。我们提供了Notch信号至少部分通过SIRPα调节巨噬细胞极化的证据。有趣的是，Notch信号通过SIRPα调节巨噬细胞对肿瘤细胞的吞噬作用，但不依赖于SHP-1。为了评估我们的发现的翻译价值，我们表达了小鼠SIRPα的胞外结构域（mSIRPαext）以阻断CD 47和SIRPα之间的相互作用。我们证明可溶性mSIRPαext多肽可以促进M1极化并增加巨噬细胞对肿瘤细胞的吞噬作用。总之，我们的研究结果为Notch介导的巨噬细胞极化的分子机制提供了新的见解，并进一步验证了SIRPα通过调节巨噬细胞极化和吞噬作用作为肿瘤治疗的靶点。
The Notch pathway plays critical roles in the development and functional modulation of myeloid cells. Previous studies have demonstrated that Notch activation promotes M1 polarization and phagocytosis of macrophages; however, the downstream molecular mechanisms mediating Notch signal remain elusive. In an attempt to identify Notch downstream targets in bone marrow-derived macrophages (BMDMs) using mass spectrometry, the signal regulatory protein α (SIRPα) appeared to respond to knockout of recombination signal-binding protein Jk (RBP-J), the critical transcription factor of Notch pathway, in macrophages. In this study, we validated that Notch activation could repress SIRPα expression likely via the Hes family co-repressors. SIRPα promoted macrophage M2 polarization, which was dependent on the interaction with CD47 and mediated by intracellular signaling through SHP-1. We provided evidence that Notch signal regulated macrophage polarization at least partially through SIRPα. Interestingly, Notch signal regulated macrophage phagocytosis of tumor cells through SIRPα but in a SHP-1-independent way. To access the translational value of our findings, we expressed the extracellular domains of the mouse SIRPα (mSIRPαext) to block the interaction between CD47 and SIRPα. We demonstrated that the soluble mSIRPαext polypeptides could promote M1 polarization and increase phagocytosis of tumor cells by macrophages. Taken together, our results provided new insights into the molecular mechanisms of notch-mediated macrophage polarization and further validated SIRPα as a target for tumor therapy through modulating macrophage polarization and phagocytosis.
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影响因子：
64.5
作者：
Majeti R;Chao MP;Alizadeh AA;Pang WW;Jaiswal S;Gibbs KD Jr;van Rooijen N;Weissman IL
通讯作者：
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影响因子：
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作者：
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影响因子：
11.2
作者：
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通讯作者：
Majeti R
miR-148a-3p 介导 notch 信号传导以促进巨噬细胞的分化和 M1 激活
影响因子：
7.3
作者：
Huang F;Zhao JL;Wang L;Gao CC;Liang SQ;An DJ;Bai J;Chen Y;Han H;Qin HY
通讯作者：
Qin HY
影响因子：
5.3
作者：
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Majeti, Ravindra