Fibronectin leucine-rich transmembrane protein 2 drives monocyte differentiation into macrophages via the UNC5B-Akt/mTOR axis.
Fibronectin leucine-rich transmembrane protein 2 drives monocyte differentiation into macrophages via the UNC5B-Akt/mTOR axis.
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富含亮氨酸的纤连蛋白跨膜蛋白2通过UNC5B-Akt/mTOR轴驱动单核细胞分化为巨噬细胞。
DOI：
10.3389/fimmu.2023.1162004
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发表时间：
2023
影响因子：
7.3
通讯作者：
Dai, Xiaoyan
中科院分区：
文献类型：
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作者：
Fang, Yaxiong;Ma, Kongyang;Huang, Yi-Min;Dang, Yuanye;Liu, Zhaoyu;Xu, Yiming;Zheng, Xi-Long;Yang, Xiangdong;Huo, Yongliang;Dai, Xiaoyan
在迁移到组织中时，造血干细胞（HSC）衍生的单核细胞分化成巨噬细胞，在确定针对外部病原体和内部刺激的先天免疫应答中起关键作用。然而，单核细胞向巨噬细胞分化的调控机制在很大程度上仍未被探索。在这里，我们揭示了以前的特点，但轴突的指导分子，纤连蛋白富含亮氨酸的跨膜蛋白2（FLRT 2），在单核细胞到巨噬细胞的成熟必不可少的作用。FLRT 2在人单核细胞系、人外周血单核细胞（PBMC）和小鼠原代单核细胞中几乎检测不到，但在完全分化的巨噬细胞中显著增加。骨髓特异性FLRT 2缺失（Flrt 2 ΔMyel）导致小鼠体内腹膜单核细胞-巨噬细胞生成减少，并伴有巨噬细胞功能受损。功能获得和丧失研究支持FLRT 2对THP-1细胞和人PBMC分化成巨噬细胞的促进作用。在机制上，FLRT 2通过其细胞外结构域（ECD）直接与Unc-5 netrin受体B（UNC 5 B）相互作用并激活Akt/mTOR信号传导。体内给予mTOR激动剂MYH 1485可逆转Flrt 2 ΔMyel小鼠中观察到的受损表型。总之，这些结果将FLRT 2鉴定为单核细胞分化为巨噬细胞的新型关键内源性调节剂。靶向FLRT 2/UNC 5 B-Akt/mTOR轴可以提供与异常单核细胞/巨噬细胞分化相关的人类疾病直接相关的潜在治疗策略。
Upon migrating into the tissues, hematopoietic stem cell (HSC)-derived monocytes differentiate into macrophages, playing a crucial role in determining innate immune responses towards external pathogens and internal stimuli. However, the regulatory mechanisms underlying monocyte-to-macrophage differentiation remain largely unexplored. Here we divulge a previously uncharacterized but essential role for an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), in monocyte-to-macrophage maturation. FLRT2 is almost undetectable in human monocytic cell lines, human peripheral blood mononuclear cells (PBMCs), and mouse primary monocytes but significantly increases in fully differentiated macrophages. Myeloid-specific deletion of FLRT2 (Flrt2ΔMyel ) contributes to decreased peritoneal monocyte-to-macrophage generation in mice in vivo, accompanied by impaired macrophage functions. Gain- and loss-of-function studies support the promoting effect of FLRT2 on THP-1 cell and human PBMC differentiation into macrophages. Mechanistically, FLRT2 directly interacts with Unc-5 netrin receptor B (UNC5B) via its extracellular domain (ECD) and activates Akt/mTOR signaling. In vivo administration of mTOR agonist MYH1485 reverses the impaired phenotypes observed in Flrt2ΔMyel mice. Together, these results identify FLRT2 as a novel pivotal endogenous regulator of monocyte differentiation into macrophages. Targeting the FLRT2/UNC5B-Akt/mTOR axis may provide potential therapeutic strategies directly relevant to human diseases associated with aberrant monocyte/macrophage differentiation.
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影响因子：
30.5
作者：
Cheung P;Schaffert S;Chang SE;Dvorak M;Donato M;Macaubas C;Foecke MH;Li TM;Zhang L;Coan JP;Schulert GS;Grom AA;Henderson LA;Nigrovic PA;Elias JE;Gozani O;Mellins ED;Khatri P;Utz PJ;Kuo AJ
通讯作者：
Kuo AJ
影响因子：
4.4
作者：
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通讯作者：
Kunkel, LM
DOI：
10.1172/jci153626
发表时间：
2022-03-15
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
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通讯作者：
Kubota Y
影响因子：
4.8
作者：
Dai, Xiaoyan;Okon, Imoh;Zou, Ming-Hui
通讯作者：
Zou, Ming-Hui
DOI：
10.1084/jem.20161855
发表时间：
2017-09-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Karmaus PWF;Herrada AA;Guy C;Neale G;Dhungana Y;Long L;Vogel P;Avila J;Clish CB;Chi H
通讯作者：
Chi H