Monocyte‐derived macrophages are the major innate immune cells that provide the first line of cellular defense against infections or injuries. These recruited macrophages at the site of inflammation are exposed to a broad range of cytokines that categorically incite a robust pro‐inflammatory response. However, macrophage pro‐inflammatory activation must be under exquisite control to avert unbridled inflammation. Thus, endogenous mechanisms must exist that rigorously preserve macrophage quiescence and yet, allow nimble pro‐inflammatory macrophage response with precise spatiotemporal control. Herein, we identify the CBP/p300‐interacting transactivator with glutamic acid/aspartic acid‐rich carboxyl‐terminal domain 2 (CITED2) as a critical intrinsic negative regulator of inflammation, which broadly attenuates pro‐inflammatory gene programs in macrophages. Our in vivo studies revealed that myeloid‐CITED2 deficiency significantly heightened macrophages and neutrophils recruitment to the site of inflammation. Our integrated transcriptomics and gene set enrichment analysis (GSEA) studies uncovered that CITED2 deficiency broadly enhances NFκB targets, IFNγ/IFNα responses, and inflammatory response gene expression in macrophages. Using complementary gain‐ and loss‐of‐function studies, we observed that CITED2 overexpression attenuate and CITED2 deficiency elevate LPS‐induced NFκB transcriptional activity and NFκB‐p65 recruitment to target gene promoter in macrophages. More importantly, blockade of NFκB signaling completely reversed elevated pro‐inflammatory gene expression in macrophages. Collectively, our findings show that CITED2 restrains NFκB activation and curtails broad pro‐inflammatory gene programs in myeloid cells.

中文翻译：

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CITED2限制了骨髓细胞中的致病性炎症基因程序

单核细胞衍生的巨噬细胞是主要的先天免疫细胞，提供细胞防御感染或损伤的第一道防线。这些在炎症部位募集的巨噬细胞暴露于范围广泛的细胞因子，这些细胞因子明确地激发了强烈的促炎反应。然而，巨噬细胞促炎激活必须受到严格控制才能避免肆无忌惮的炎症。因此，必须存在严格保持巨噬细胞静止状态的内源性机制，同时允许具有精确时空控制的灵活促炎巨噬细胞反应。在此，我们将 CBP/p300 相互作用的反式激活因子与富含谷氨酸/天冬氨酸的羧基末端结构域 2（CITED2）鉴定为炎症的关键内在负调节因子，广泛减弱巨噬细胞中的促炎基因程序。我们的体内研究表明，myeloid-CITED2 缺乏显着增加了巨噬细胞和中性粒细胞向炎症部位的募集。我们的综合转录组学和基因集富集分析 (GSEA) 研究发现，CITED2 缺陷广泛增强了巨噬细胞中的 NFκB 靶标、IFNγ/IFNα 反应和炎症反应基因表达。使用互补的功能获得和功能丧失研究，我们观察到 CITED2 过表达减弱和 CITED2 缺乏提高 LPS 诱导的 NFκB 转录活性和 NFκB-p65 募集到巨噬细胞中的靶基因启动子。更重要的是，阻断 NFκB 信号完全逆转了巨噬细胞中升高的促炎基因表达。总的来说，