Chen Yuhan, Liu Wen, Wang Yiwu, Zhang Luo, Wei Jun, Zhang Xueli, He Fuchu, Zhang Lingqiang
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing, China; Bayi Children's Hospital, Army General Hospital, Beijing, China.
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing, China.
Cell Signal. 2017 May;33:107-121. doi: 10.1016/j.cellsig.2017.02.015. Epub 2017 Feb 14.
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-γ) 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-κB 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.
巨噬细胞可塑性的重要性尽管是最近才被发现，但已在生理和病理环境中广泛存在的一系列生物学过程中得到凸显。巨噬细胞的极化激活和失活对免疫和炎症反应具有深远影响，在过去几年中已有几条主要途径得到阐明。然而，调控巨噬细胞极化的转录调节机制仍处于初步阶段。在本研究中，我们确定酪蛋白激酶2相互作用蛋白1（CKIP-1）是一种操纵巨噬细胞形态形成的分子开关。在人和小鼠巨噬细胞中，促炎M1刺激物（脂多糖和干扰素-γ）强烈诱导CKIP-1表达，而M2刺激物（白细胞介素-4和白细胞介素-13）则强烈抑制其表达。功能获得和丧失研究表明，CKIP-1是脂多糖诱导的促炎基因最佳激活的先决条件，它以NF-κB依赖的方式发挥作用。此外，CKIP-1通过负向调节巨噬细胞中的JAK1-STAT6激活来抑制抗炎基因表达。综上所述，这些数据整合了CKIP-1的表达和功能，将其作为巨噬细胞极化的一种新型转录调节因子，并确定了一个由CKIP-1以及极化途径中M1和M2巨噬细胞效应器的关键调节因子组成的双反馈回路。此外，CKIP-1在脂多糖介导的脓毒症和佛波酯介导的皮肤炎症中的抑制作用为急性炎症的治疗提供了一个新靶点。
