正文:3.3 Jmjd3表观遗传修饰对M2型巨噬细胞的调控
近些年来的研究表明,表观遗传学机制也能够调控巨噬细胞内基因的表达。目前研究较多的有甲基化修饰、乙酰化修饰等[6]。
Jmjd3作为一种组蛋白三的赖氨酸第27位点(H3K27)的去甲基化酶,能够催化H3K27me3转变为H3K27me1,使得相关基因活化。在IL-4诱导下,Jmjd3高水平表达并且向M2相关功能基因的启动子区域募集,由于STAT6是细胞因子IL-4介导的信号通路的主要转录因子,故推测IL-4依赖性的Jmjd3高表达是通过STAT6信号途径实现的[28]。另有研究发现Jmjd3可通过影响IRF4基因的开放参与调控巨噬细胞向M2型巨噬细胞的分化[32]。
3.4 SOCS对M1/M2的转录调控
细胞因子信号抑制因子(SOCS)是一类免疫抑制分子,参与T细胞分化调节等[4]。目前已知的SOCS家族共有8个成员,细胞因子信号通路能调节该家族蛋白的表达,而SOCS蛋白通过直接结合活化的JAK激酶或磷酸化的受体来抑制JAK/STAT信号转导通路的活性[33]。其中SOCS1通过阻断JAK家族成员的酪氨酸激酶活性抑制IFN-γ信号[34],而IL-4能够上调SOCS1。而IFN-γ和LPS一起刺激能够够上调SOCS3。SOCS1和SOCS3活化后分别抑制STAT1和STAT3,进而分别抑制巨噬细胞向M1型和M2型极化。
另外,研究发现SOCS3缺失可导致LPS能够诱导内毒素耐受,而在SOCS2敲除的小鼠中M1型巨噬细胞增加,说明SOCS3对于M1型巨噬细胞的活化是必需的,而SOCS1、SCOS2对于M2型的活化是必需的[3]。
4 结语
可塑性和异质性是巨噬细胞本身以及活化后的明显特征。巨噬细胞在不同微环境下,经不同刺激物诱导可差异性地发生活化,活化后表型和性质不同,并能够发挥不同的促炎或抗炎、抗肿瘤或促肿瘤的功能。其中M1型巨噬细胞主要发挥抗感染和抗肿瘤的生物效应,而M2型巨噬细胞则能够促进血管生成以及促进肿瘤的发展。目前认为M1和M2是巨噬细胞极化的两个极端,而大部分病理状态下,巨噬细胞处于动态的变化中,如在动脉粥样硬化疾病中,早期发挥作用的主要是M1型,而在晚期发挥作用的主要是M2型。因此充分阐明人类疾病过程中的巨噬细胞极化亚型及其极化机制,设计靶向于巨噬细胞本身或调控的分子策略,能够为治疗感染等疾病提供新的途径和手段。
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