Regulation of Versican Expression in Macrophages is Mediated by Canonical Type I Interferon Signaling via ISGF3.
Regulation of Versican Expression in Macrophages is Mediated by Canonical Type I Interferon Signaling via ISGF3.
复制标题
巨噬细胞中多功能蛋白聚糖表达的调节是由典型的 I 型干扰素信号通过 ISGF3 介导的。
DOI：
10.1101/2024.03.14.585097
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Altemeier,WilliamA
中科院分区：
文献类型：
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作者：
Chang,MaryY;Chan,ChristinaK;Brune,JourdanE;Manicone,AnneM;Bomsztyk,Karol;Frevert,CharlesW;Altemeier,WilliamA
越来越多的证据支持多功能蛋白聚糖作为炎症反应的重要组成部分的作用，其促炎和抗炎作用取决于所研究的系统或疾病的具体情况。我们的目标是了解巨噬细胞源性多功能蛋白聚糖的调节及其在先天免疫中的作用。在以前的工作中，我们表明，LPS触发涉及Toll样受体（TLR）4，Trif适配器，I型干扰素和I型干扰素受体的信号级联反应，导致多功能蛋白聚糖表达增加的巨噬细胞。在本研究中，我们使用了染色质免疫沉淀，siRNA，化学抑制剂和小鼠模型的方法相结合，以调查I型干扰素受体下游的调节事件，以更好地定义控制多功能蛋白聚糖表达的机制。结果表明，通过干扰素刺激的基因因子3（ISGF3），Irf9，Stat1和Stat2的异源三聚体转录因子复合物，典型的I型干扰素信号传导的转录调节，控制多功能蛋白聚糖在暴露于LPS的巨噬细胞中的表达。该途径不依赖于MAPK信号传导，MAPK信号传导已被证明调节其他细胞类型中的多功能蛋白聚糖表达。多功能蛋白聚糖mRNA的稳定性也可能有助于延长多功能蛋白聚糖在巨噬细胞中的表达。这些研究结果强烈支持巨噬细胞衍生的多功能蛋白聚糖作为I型干扰素刺激基因的作用，并进一步了解多功能蛋白聚糖在调节inflammation.NEW和值得注意的是，我们报告的新发现，多功能蛋白聚糖的表达是由干扰素刺激的基因因子3（ISGF3）手臂的典型I型IFN信号在LPS刺激的巨噬细胞。该途径与控制其他细胞类型中多功能蛋白聚糖表达的机制不同。这表明巨噬细胞衍生的多功能蛋白聚糖可能在限制潜在的过度炎症反应方面发挥作用。详细了解多功能蛋白聚糖在不同细胞中的表达是如何调节的，可能会导致增强其抗炎特性的独特方法。
Growing evidence supports a role for versican as an important component of the inflammatory response, with both pro- and anti-inflammatory roles depending on the specific context of the system or disease under investigation. Our goal is to understand the regulation of macrophage-derived versican and the role it plays in innate immunity. In previous work, we showed that LPS triggers a signaling cascade involving Toll-like receptor (TLR)4, the Trif adaptor, type I interferons, and the type I interferon receptor, leading to increased versican expression by macrophages. In the present study, we used a combination of chromatin immunoprecipitation, siRNA, chemical inhibitors, and mouse model approaches to investigate the regulatory events downstream of the type I interferon receptor to better define the mechanism controlling versican expression. Results indicate that transcriptional regulation by canonical type I interferon signaling via interferon-stimulated gene factor 3 (ISGF3), the heterotrimeric transcription factor complex of Irf9, Stat1, and Stat2, controls versican expression in macrophages exposed to LPS. This pathway is not dependent on MAPK signaling, which has been shown to regulate versican expression in other cell types. The stability of versican mRNA may also contribute to prolonged versican expression in macrophages. These findings strongly support a role for macrophage-derived versican as a type I interferon-stimulated gene and further our understanding of versican’s role in regulating inflammation.NEW & NOTEWORTHYWe report the novel finding that versican expression is regulated by the interferon-stimulated gene factor 3 (ISGF3) arm of canonical type I Ifn signaling in LPS-stimulated macrophages. This pathway is distinct from mechanisms that control versican expression in other cell types. This suggests that macrophage-derived versican may play a role in limiting a potentially excessive inflammatory response. The detailed understanding of how versican expression is regulated in different cells could lead to unique approaches for enhancing its anti-inflammatory properties.