Department of Biological Sciences, Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina, United States of America.
Department of Biological Sciences, Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina, United States of America; Center for Integrated Medical Research, Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
PLoS One. 2014 Apr 15;9(4):e94982. doi: 10.1371/journal.pone.0094982. eCollection 2014.
Macrophages play diverse roles in tissue homeostasis and immunity, and canonically activated macrophages are critically associated with acute inflammatory responses. It is known that activated macrophages undergo cell death after transient activation in some settings, and the viability of macrophages impacts on inflammatory status. Here we report that TGFβ- activated kinase (TAK1) activators, TAK1-binding protein 1 (TAB1) and TAK1-binding protein 2 (TAB2), are critical molecules in the regulation of activated macrophage survival. While deletion of Tak1 induced cell death in bone marrow derived macrophages even without activation, Tab1 or Tab2 deletion alone did not profoundly affect survival of naïve macrophages. However, in lipopolysaccharide (LPS)-activated macrophages, even single deletion of Tab1 or Tab2 resulted in macrophage death with both necrotic and apoptotic features. We show that TAB1 and TAB2 were redundantly involved in LPS-induced TAK1 activation in macrophages. These results demonstrate that TAK1 activity is the key to activated macrophage survival. Finally, in an in vivo setting, Tab1 deficiency impaired increase of peritoneal macrophages upon LPS challenge, suggesting that TAK1 complex regulation of macrophages may participate in in vivo macrophage homeostasis. Our results demonstrate that TAB1 and TAB2 are required for activated macrophages, making TAB1 and TAB2 effective targets to control inflammation by modulating macrophage survival.
巨噬细胞在组织稳态和免疫中发挥多种作用，经典激活的巨噬细胞与急性炎症反应密切相关。众所周知，在某些情况下，短暂激活后，活化的巨噬细胞会发生细胞死亡，而巨噬细胞的存活能力会影响炎症状态。在这里，我们报告 TGFβ-激活激酶（TAK1）激活剂 TAK1 结合蛋白 1（TAB1）和 TAK1 结合蛋白 2（TAB2）是调节活化的巨噬细胞存活的关键分子。虽然骨髓来源的巨噬细胞中 Tak1 的缺失即使在没有激活的情况下也会诱导细胞死亡，但 Tab1 或 Tab2 的缺失单独并不会显著影响原始巨噬细胞的存活。然而，在脂多糖（LPS）激活的巨噬细胞中，即使 TAB1 或 TAB2 的单一缺失也会导致巨噬细胞死亡，具有坏死和凋亡特征。我们表明 TAB1 和 TAB2 参与 LPS 诱导的巨噬细胞中 TAK1 的激活。这些结果表明 TAK1 活性是活化巨噬细胞存活的关键。最后，在体内环境中，Tab1 缺失会损害 LPS 刺激后腹腔巨噬细胞的增加，表明 TAK1 复合物对巨噬细胞的调节可能参与体内巨噬细胞稳态。我们的结果表明 TAB1 和 TAB2 是活化的巨噬细胞所必需的，这使得 TAB1 和 TAB2 成为通过调节巨噬细胞存活来控制炎症的有效靶点。
