Carson William F, Cavassani Karen A, Soares Elyara M, Hirai Soichiro, Kittan Nicolai A, Schaller Matthew A, Scola Melissa M, Joshi Amrita, Matsukawa Akihiro, Aronoff David M, Johnson Craig N, Dou Yali, Gallagher Katherine A, Kunkel Steven L
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
J Immunol. 2017 Sep 1;199(5):1865-1874. doi: 10.4049/jimmunol.1601272. Epub 2017 Jul 21.
Macrophages are critical immune cells for the clearance of microbial pathogens and cellular debris from peripheral tissues. Macrophage inflammatory responses are governed by gene expression patterns, and these patterns are often subject to epigenetic control. Chromatin modifications, such as histone methylation, regulate gene accessibility in macrophages, and macrophage polarization is governed in part by the expression and function of chromatin-modifying enzymes. The histone methyltransferase mixed-lineage leukemia 1 (MLL1) preferentially modifies lysine residue 4 on the unstructured protein tail of histone H3. MLL1 expression and function have been shown to be governed by signal transduction pathways that are activated by inflammatory stimuli, such as NF-κB. Therefore, we sought to investigate the role of MLL1 in mediating macrophage inflammatory responses. Bone marrow-derived macrophages from mice with a targeted MLL1 gene knockout (Lys2-Cre MLL1) exhibited decreased proinflammatory gene expression with concurrent decreases in activating histone methylation. However, MLL1-deficient macrophages also exhibited increased phagocytic and bacterial killing activity in vitro. RNA profiling of MLL1-knockout macrophages identified numerous genes involved with inflammatory responses whose expression was altered in response to TLR ligands or proinflammatory cytokines, including STAT4. STAT4-dependent cytokines, such as type I IFNs were able to drive MLL1 expression in macrophages, and MLL1-knockout macrophages exhibited decreased activating histone methylation in the STAT4 promoter. These results implicate an important role for MLL1-dependent epigenetic regulation of macrophage antimicrobial functions.
巨噬细胞是清除外周组织中微生物病原体和细胞碎片的关键免疫细胞。巨噬细胞的炎症反应受基因表达模式的调控，而这些模式通常受到表观遗传控制。染色质修饰，如组蛋白甲基化，调节巨噬细胞中的基因可及性，巨噬细胞极化部分受染色质修饰酶的表达和功能支配。组蛋白甲基转移酶混合谱系白血病1（MLL1）优先修饰组蛋白H3无结构蛋白尾部的赖氨酸残基4。已表明MLL1的表达和功能受炎症刺激（如NF-κB）激活的信号转导通路支配。因此，我们试图研究MLL1在介导巨噬细胞炎症反应中的作用。来自靶向MLL1基因敲除小鼠（Lys2-Cre MLL1）的骨髓来源巨噬细胞表现出促炎基因表达降低，同时激活组蛋白甲基化也降低。然而，MLL1缺陷型巨噬细胞在体外还表现出吞噬和细菌杀伤活性增加。对MLL1敲除巨噬细胞的RNA分析确定了许多与炎症反应相关的基因，其表达因TLR配体或促炎细胞因子（包括STAT4）而改变。STAT4依赖性细胞因子，如I型干扰素，能够驱动巨噬细胞中MLL1的表达，并且MLL1敲除巨噬细胞在STAT4启动子中表现出激活组蛋白甲基化降低。这些结果表明MLL1依赖性表观遗传调控在巨噬细胞抗菌功能中起重要作用。
