Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages.
Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages.
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DOI：
10.1042/bcj20160646
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发表时间：
2017-02-15
期刊：
影响因子：
--
通讯作者：
Clark K
中科院分区：
文献类型：
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作者：
Darling NJ;Toth R;Arthur JS;Clark K
盐诱导激酶（SIK）控制着调节巨噬细胞极化的新型分子开关。 SIK 的药理抑制会诱导巨噬细胞表型，其特征是分泌高水平的抗炎细胞因子，包括白细胞介素 (IL)-10，以及分泌极低水平的促炎细胞因子，例如肿瘤坏死因子 α。因此，SIK 代表了治疗巨噬细胞驱动疾病的有吸引力的新药物靶点，但三种亚型（SIK1、SIK2 或 SIK3）中哪一种适合作为靶点仍然未知。为了解决这个问题，我们开发了 SIK1、SIK2 和 SIK3 的敲入 (KI) 小鼠，其中我们引入了一种突变，使酶失去催化活性。对单 KI 和双 KI 小鼠的原代巨噬细胞的表征表明，所有三种 SIK 亚型，特别是 SIK2 和 SIK3，都有助于巨噬细胞极化。此外，我们发现，与成熟巨噬细胞中的抑制相比，巨噬细胞分化过程中抑制SIK2和SIK3大大增强了IL-10的产生。有趣的是，巨噬细胞在 SIK 抑制剂 MRT199665 和 HG-9-91-01 存在下分化，仍然产生大量的 IL-10，但促炎细胞因子的水平非常低，即使在通过去除药物重新激活 SIK 后也是如此。我们的数据强调了 SIK2 和 SIK3 通过阻止巨噬细胞分化为有效且稳定的抗炎表型，在先天免疫中发挥着不可或缺的作用。
The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of very low levels of pro-inflammatory cytokines, such as tumour necrosis factor α. The SIKs, therefore, represent attractive new drug targets for the treatment of macrophage-driven diseases, but which of the three isoforms, SIK1, SIK2 or SIK3, would be appropriate to target remains unknown. To address this question, we developed knock-in (KI) mice for SIK1, SIK2 and SIK3, in which we introduced a mutation that renders the enzymes catalytically inactive. Characterization of primary macrophages from the single and double KI mice established that all three SIK isoforms, and in particular SIK2 and SIK3, contribute to macrophage polarization. Moreover, we discovered that inhibition of SIK2 and SIK3 during macrophage differentiation greatly enhanced the production of IL-10 compared with their inhibition in mature macrophages. Interestingly, macrophages differentiated in the presence of SIK inhibitors, MRT199665 and HG-9-91-01, still produced very large amounts of IL-10, but very low levels of pro-inflammatory cytokines, even after the SIKs had been reactivated by removal of the drugs. Our data highlight an integral role for SIK2 and SIK3 in innate immunity by preventing the differentiation of macrophages into a potent and stable anti-inflammatory phenotype.