Activated Macrophage Survival Is Coordinated by TAK1 Binding Proteins

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（Macrophages）在组织稳态与免疫过程中发挥多样功能，而经典活化巨噬细胞（canonically activated macrophages）与急性炎症反应密切相关。已知在部分情境下，活化的巨噬细胞会在短暂激活后发生细胞死亡，且巨噬细胞的存活状态会影响炎症状况。本研究发现，转化生长因子β活化激酶（TGFβ-activated kinase，TAK1）的激活因子——TAK1结合蛋白1（TAB1）与TAK1结合蛋白2（TAB2），是调控活化巨噬细胞存活的关键分子。尽管Tak1基因敲除会在未激活状态下诱导骨髓来源巨噬细胞发生细胞死亡，但单独敲除Tab1或Tab2并不会显著影响未活化巨噬细胞的存活。然而在脂多糖（LPS）活化的巨噬细胞中，即使单独敲除Tab1或Tab2，都会导致巨噬细胞发生兼具坏死与凋亡特征的细胞死亡。本研究证实，TAB1与TAB2在巨噬细胞中以功能冗余的方式参与LPS诱导的TAK1激活过程。上述结果表明，TAK1的活性是决定活化巨噬细胞存活的核心因素。最后，在体内实验中，Tab1基因缺陷会抑制LPS刺激下腹腔巨噬细胞的数量扩增，这提示TAK1复合物对巨噬细胞的调控可能参与体内巨噬细胞的稳态维持。本研究结果证实，TAB1与TAB2是活化巨噬细胞存活所必需的分子，这使得TAB1与TAB2成为通过调控巨噬细胞存活来控制炎症的有效靶点。