A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair
A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair
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DOI：
10.1073/pnas.0908641106
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发表时间：
2009-10-13
影响因子：
11.1
通讯作者：
Nerlov, Claus
中科院分区：
文献类型：
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作者：
Ruffell, Daniela;Mourkioti, Foteini;Nerlov, Claus
巨噬细胞通过清除坏死细胞在解决组织损伤方面发挥重要作用，从而为组织再生铺平道路。巨噬细胞还通过获得抗炎或M2表型直接支持新组织的形成以取代损伤，其特征在于包括IL-10、IL-13受体和精氨酸酶1的基因表达程序。我们报告说，删除两个CREB结合位点的Cebpb启动子废除Cebpb诱导巨噬细胞活化。这阻断了M2特异性Msr1、Il10、II13ra和Arg-1基因的下游诱导，而炎症（M1）基因Il1、Il6、Tnfa和Il12不受影响。携带突变的Cebpb启动子（β Delta Cre）的小鼠从受伤的肌肉中去除坏死组织，但在肌纤维再生方面表现出严重缺陷。在肌肉细胞中Cebpb基因的条件性缺失不影响再生，表明导致肌肉修复的C/EBP β级联是肌肉外在的。虽然β Δ Cre巨噬细胞有效地浸润损伤的肌肉，但它们不能上调Cebpb，导致Arg-1表达降低。因此，CREB介导的Cebpb表达的诱导在浸润性巨噬细胞中是必需的，用于上调M2特异性基因和肌肉再生，从而在这两个过程之间提供直接的遗传联系。
Macrophages play an essential role in the resolution of tissue damage through removal of necrotic cells, thus paving the way for tissue regeneration. Macrophages also directly support the formation of new tissue to replace the injury, through their acquisition of an anti-inflammatory, or M2, phenotype, characterized by a gene expression program that includes IL-10, the IL-13 receptor, and arginase 1. We report that deletion of two CREB-binding sites from the Cebpb promoter abrogates Cebpb induction upon macrophage activation. This blocks the downstream induction of M2-specific Msr1, Il10, II13ra, and Arg-1 genes, whereas the inflammatory (M1) genes Il1, Il6, Tnfa, and Il12 are not affected. Mice carrying the mutated Cebpb promoter (beta Delta Cre) remove necrotic tissue from injured muscle, but exhibit severe defects in muscle fiber regeneration. Conditional deletion of the Cebpb gene in muscle cells does not affect regeneration, showing that the C/EBP beta cascade leading to muscle repair is muscle-extrinsic. While beta Delta Cre macrophages efficiently infiltrate injured muscle they fail to upregulate Cebpb, leading to decreased Arg-1 expression. CREB-mediated induction of Cebpb expression is therefore required in infiltrating macrophages for upregulation of M2-specific genes and muscle regeneration, providing a direct genetic link between these two processes.