Casein Kinase 2 Interacting Protein-1 regulates M1 and M2 inflammatory macrophage polarization
Casein Kinase 2 Interacting Protein-1 regulates M1 and M2 inflammatory macrophage polarization
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DOI：
10.1016/j.cellsig.2017.02.015
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发表时间：
2017-05-01
影响因子：
4.8
通讯作者：
Zhang, Lingqiang
中科院分区：
文献类型：
--
作者：
Chen, Yuhan;Liu, Wen;Zhang, Lingqiang
巨噬细胞可塑性的重要性，虽然是最近才发现的，已被强调在生理和病理环境中的广泛的生物过程。巨噬细胞的极化激活和失活对免疫和炎症反应有着深远的影响，在过去的几年里，几个主要的途径被阐明。然而，巨噬细胞极化的转录调控机制仍然是初步的。在这项研究中，我们确定酪蛋白激酶2相互作用蛋白1（CKIP-1）作为一个分子切换操纵巨噬细胞物种形成。在人和鼠巨噬细胞中，促炎性M1刺激（LPS和IFN-γ）强烈诱导CKIP-1表达，M2刺激（IL-4和IL-13）强烈抑制CKIP-1表达。功能获得和丧失研究表明，CKIP-1是最佳LPS诱导的促炎基因活化的先决条件，其以NF-κ B依赖性方式发挥作用。此外，CKIP-1通过负调节巨噬细胞中JAK 1-STAT 6的活化来抑制抗炎基因的表达。总之，这些数据整合了CKIP-1表达和功能，作为一种新的巨噬细胞极化的转录调节因子，并确定了一个由CKIP-1和极化途径中M1和M2巨噬细胞效应物的关键调节因子组成的双反馈回路。此外，CKIP-1在LPS介导的脓毒症和TPA介导的皮肤中的抑制作用为急性炎症的治疗提供了新的靶点。(C)2017爱思唯尔公司All rights reserved.
The importance of macrophage plasticity, albeit being discovered recently, has been highlighted in a broad spectrum of biological processes operative in physiological and pathological environments. Macrophage polarized activation and inactivation has profound effects on immune and inflammatory responses with several major pathways being elucidated in the past few years. However, transcriptional regulation mechanisms governing macrophage polarization is still preliminary. In this study, we identify the Casein Kinase 2 Interacting Protein 1 (CKIP-1) as a molecular toggle manipulating macrophage speciation. CKIP-1 expression was strongly induced by pro-inflammatory M1 stimuli (LPS and IFN-gamma) and robustly suppressed by M2 stimuli (IL-4 and IL-13) in human and murine macrophage. Gain and loss of function studies suggest that CKIP-1 is a prerequisite for optimal LPS-induced pro -inflammatory gene activation, which exhibits its roles in a NF-kB dependent manner. Furthermore, CKIP-1 inhibits anti-inflammatory gene expression by negatively regulating JAK1-STAT6 activation in macrophages. Taken together, these data integrated CKIP-1 expression and function as a novel transcriptional regulator of macrophage polarization and identified a double feedback loop consisting of CKIP-1 and the key regulators of the M1 and M2 macrophage effectors in polarization pathway. Moreover, the inhibitory roles of CKIP-1 in LPS-mediated sepsis and TPA-mediated cutaneous provide a new target for treatments of acute inflammation. (C) 2017 Elsevier Inc. All rights reserved.