Tribbles homolog 1 deficiency modulates function and polarization of murine bone marrow-derived macrophages
Tribbles homolog 1 deficiency modulates function and polarization of murine bone marrow-derived macrophages
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DOI：
10.1074/jbc.ra117.000703
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发表时间：
2018-07-20
影响因子：
4.8
通讯作者：
Burkhardt, Ralph
中科院分区：
文献类型：
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作者：
Arndt, Lilli;Dokas, Janine;Burkhardt, Ralph
巨噬细胞是先天免疫和炎症反应所必需的，并分化成各种功能表型。Tribbles同源物1（Trib 1）是哺乳动物Tribbles同源物假激酶家族的一员，参与细胞分化、增殖和代谢的调节，但其在巨噬细胞生物学中的作用尚未完全阐明。在这里，我们研究了Trib 1缺陷对巨噬细胞功能和M1/M2极化的影响。来自Trib 1缺陷（Trib 1（-/-））小鼠的骨髓源性巨噬细胞（BMDM）表现出吞噬能力升高，与几种清道夫受体的上调相关。同时，Trib 1（-/-）BMDM中修饰低密度脂蛋白的摄取增加。Trib 1（-/-）巨噬细胞在趋化因子MCP-1的存在下也表现出迁移减少，这与MCP-1受体Ccr 2的表达减少有关。此外，Trib 1缺陷减弱BMDM对M1和M2刺激的反应; LPS/IFN刺激后M1标记基因Il 6、Il 1b和Nos 2的诱导以及IL-4刺激后M2标记基因Cd 206、Fizz 1和Arg 1的诱导减少。在功能上，Trib 1缺乏减少促炎细胞因子（IL-6，TNF，IL-1和CXCL 1）的分泌，并减少M1极化巨噬细胞中一氧化氮和活性氧的产生。支持减弱的M2表型，IL-4刺激的Trib 1（-/-）巨噬细胞分泌较少的IL-10和TGF。从机制上讲，Trib 1（-/-）BMDM显示较低水平的Janus激酶1（JAK 1），导致LPS/IFN介导的STAT 1信号转导的激活减少。同样，在M2极化Trib 1（-/-）BMDM中观察到JAK 1水平降低沿着STAT 6和STAT 3活化降低。我们的研究结果表明，Trib 1通过JAK/STAT信号通路广泛控制巨噬细胞M1/M2极化。
Macrophages are essential for innate immunity and inflammatory responses and differentiate into various functional phenotypes. Tribbles homolog 1 (Trib1), a member of the mammalian Tribbles homolog pseudokinase family, has been implicated in regulation of cell differentiation, proliferation, and metabolism, but its role in macrophage biology has not been fully elucidated. Here, we investigated the consequences of Trib1 deficiency on macrophage functions and M1/M2 polarization. Bone marrow-derived macrophages (BMDMs) from Trib1-deficient (Trib1(-/-)) mice exhibited elevated phagocytic capacity, correlating with up-regulation of several scavenger receptors. Concomitantly, uptake of modified low-density lipoprotein was increased in Trib1(-/-) BMDMs. Trib1(-/-) macrophages also exhibited diminished migration in the presence of the chemokine MCP-1, associated with reduced expression of the MCP-1 receptor Ccr2. Furthermore, Trib1 deficiency attenuated the response of BMDMs to both M1 and M2 stimuli; induction of the M1-marker genes Il6, Il1b, and Nos2 upon LPS/IFN stimulation and of the M2-marker genes Cd206, Fizz1, and Arg1 upon IL-4 stimulation was reduced. Functionally, Trib1 deficiency decreased secretion of proinflammatory cytokines (IL-6, TNF, IL-1, and CXCL1) and reduced nitric oxide and reactive oxygen species production in M1-polarized macrophages. Supporting the attenuated M2 phenotype, IL-4-stimulated Trib1(-/-) macrophages secreted less IL-10 and TGF. Mechanistically, Trib1(-/-) BMDMs displayed lower levels of Janus kinase 1 (JAK1), resulting in reduced activation of LPS/IFN-mediated STAT1 signaling. Likewise, decreased levels of JAK1 along with lower activation of STAT6 and STAT3 were observed in M2-polarized Trib1(-/-) BMDMs. Our findings suggest that Trib1 extensively controls macrophage M1/M2 polarization via the JAK/STAT signaling pathway.