TGFß reprograms TNF stimulation of macrophages towards osteoclastogenesis [CUT&RUN]

TNF plays a key role in inflammation and bone resorption. However, the mechanisms regulating TNF-mediated osteoclastogenesis remain largely unclear because its direct osteoclastogenic ability is weak. Here, we found that TGFß priming enables TNF to effectively induce osteoclastogenesis from macrophages, independently of the osteoclastogenic action of RANKL. Lack of TGFß signaling in macrophages suppresses inflammatory, but not physiological, osteoclastogenesis and bone resorption in vivo. Mechanistically, TGFß priming reprograms macrophage response to TNF towards osteoclastogenesis by remodeling chromatin accessibility and histone modification. TGFß and TNF induce an unconventional osteoclastogenic program, which includes the suppression of the TNF-induced IRF1-IFNß-IFN stimulated gene (ISG) axis, promotion of IRF8 degradation and B-Myb induction. These mechanisms are present in RA, in which TGFß level is elevated and correlated with osteoclast activity. Our findings identify a function and mechanism of action for TGFß in TNF-mediated inflammatory osteoclastogenesis, and open avenues for selective treatment of inflammatory bone loss. Overall design: Analysis of transcriptional changes in human macrophages with or without TGFb priming in the presence of TNF

肿瘤坏死因子（Tumor Necrosis Factor, TNF）在炎症反应与骨吸收过程中发挥关键调控作用。然而，TNF介导的破骨细胞生成调控机制仍不甚明确，因其直接诱导破骨细胞生成的能力较弱。本研究发现，转化生长因子β（Transforming Growth Factor β, TGFβ）预处理可使TNF有效诱导巨噬细胞生成破骨细胞，且该过程不依赖核因子κB受体活化因子配体（Receptor Activator of Nuclear Factor κB Ligand, RANKL）的破骨细胞生成活性。巨噬细胞中TGFβ信号通路的缺失，会在体内抑制炎症性而非生理性的破骨细胞生成与骨吸收。从分子机制层面而言，TGFβ预处理通过重塑染色质可及性与组蛋白修饰模式，重编程巨噬细胞对TNF的应答方向，使其偏向破骨细胞生成程序。TGFβ与TNF可诱导一种非常规的破骨细胞生成通路，该通路包含抑制TNF诱导的干扰素调节因子1（Interferon Regulatory Factor 1, IRF1）-干扰素β（Interferon β, IFNβ）-干扰素刺激基因（Interferon Stimulated Gene, ISG）轴、促进干扰素调节因子8（Interferon Regulatory Factor 8, IRF8）降解以及诱导B-Myb表达。上述机制在类风湿关节炎（Rheumatoid Arthritis, RA）中存在，该疾病患者体内TGFβ水平升高，且与破骨细胞活性呈正相关。本研究明确了TGFβ在TNF介导的炎症性破骨细胞生成中的功能与作用机制，为炎症性骨丢失的选择性治疗开辟了新方向。实验整体设计：分析经与未经TGFβ预处理的人巨噬细胞在TNF存在条件下的转录组变化。