Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction.
Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction.
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Gab 2（Grb 2-Associated Binder 2）在炎症信号传导和内皮功能障碍中发挥关键作用
DOI：
10.1161/atvbaha.121.316153
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发表时间：
2021-06
期刊：
影响因子：
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通讯作者：
Pendurthi UR
中科院分区：
文献类型：
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作者：
Kondreddy V;Magisetty J;Keshava S;Rao LVM;Pendurthi UR
文本中提供了补充数字内容。为了应对炎症损伤，内皮细胞表达细胞粘附分子和 TF（组织因子），导致白细胞与内皮的粘附增加并激活凝血。凝血增强可能进一步加剧炎症。识别驱动炎症和凝血的关键信号分子可能有助于制定有效的治疗策略来治疗炎症和血栓性疾病。目前研究的目的是确定 Gab2（Grb2 相关的 binder2）的作用，已知 Gab2 在生长因子和抗原受体引发的信号传导、炎症信号传导途径及其对血管功能障碍的影响中发挥着至关重要的作用。用 TNFα（肿瘤坏死因子 α）、IL（白细胞介素）-1β 或脂多糖 (LPS) 处理 WT（野生型）和 Gab2 沉默的内皮细胞。分析炎症信号通路中关键信号蛋白的激活以及细胞粘附分子、TF 和炎症细胞因子的表达。 Gab2−/− 和 WT 同窝小鼠接受 LPS 或肺炎链球菌（肺炎链球菌）攻击，并评估炎症参数和凝血激活。内皮细胞中的 Gab2 沉默显着减弱 TNFα 诱导、IL-1β 诱导和 LPS 诱导的 TF、细胞粘附分子和炎症细胞因子/趋化因子的表达。 Gab2 沉默抑制 TNFα 诱导、IL-1β 诱导和 LPS 诱导的 TAK1（转化生长因子 β 激活激酶 1）磷酸化和泛素化以及 MAPK（丝裂原激活蛋白激酶）和 NF-κB（核因子 kappa B）的激活。免疫沉淀研究表明 Src 激酶 Fyn 磷酸化 Gab2。 Gab2−/− 小鼠免受 LPS 或肺炎链球菌诱导的血管通透性、中性粒细胞浸润、凝血酶生成、NET 形成、细胞因子产生和肺损伤的影响。我们的研究首次发现 Gab2 整合了多种炎症受体的信号并调节血管炎症和血栓形成。
Supplemental Digital Content is available in the text. In response to inflammatory insult, endothelial cells express cell adhesion molecules and TF (tissue factor), leading to increased adhesion of leukocytes to the endothelium and activation of coagulation. Enhanced coagulation could further exacerbate inflammation. Identifying key signaling molecule(s) that drive both inflammation and coagulation may help devise effective therapeutic strategies to treat inflammatory and thrombotic disorders. The aim of the current study is to determine the role of Gab2 (Grb2-associated binder2), which is known to play a crucial role in the signaling evoked by growth factors and antigen receptors, in inflammatory signaling pathways and its contribution to vascular dysfunction. WT (wild type) and Gab2-silenced endothelial cells were treated with TNFα (tumor necrosis factor alpha), IL (interleukin)-1β, or lipopolysaccharide (LPS). Activation of key signaling proteins in the inflammatory signaling pathways and expression of cell adhesion molecules, TF, and inflammatory cytokines were analyzed. Gab2−/− and WT littermate mice were challenged with LPS or S pneumoniae (Streptococcus pneumoniae), and parameters of inflammation and activation of coagulation were assessed. Gab2 silencing in endothelial cells markedly attenuated TNFα-induced, IL-1β–induced, and LPS-induced expression of TF, cell adhesion molecules, and inflammatory cytokines/chemokines. Gab2 silencing suppressed TNFα-induced, IL-1β–induced, and LPS-induced phosphorylation and ubiquitination of TAK1 (transforming growth factor beta-activated kinase 1) and activation of MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor kappa B). Immunoprecipitation studies revealed that the Src kinase Fyn phosphorylates Gab2. Gab2−/− mice are protected from LPS or S pneumoniae–induced vascular permeability, neutrophil infiltration, thrombin generation, NET formation, cytokine production, and lung injury. Our studies identify, for the first time, that Gab2 integrates signaling from multiple inflammatory receptors and regulates vascular inflammation and thrombosis.
影响因子：
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作者：
Schjeide, Brit-Maren M.;Hooli, Basavaraj;Parkinson, Michele;Hogan, Meghan F.;DiVito, Jason;Mullin, Kristina;Blacker, Deborah;Tanzi, Rudolph E.;Bertram, Lars
通讯作者：
Bertram, Lars