Activated macrophage survival is coordinated by TAK1 binding proteins

• Published in: PloS one Vol. 9; no. 4; p. e94982
• Main Authors: Mihaly, September R, Morioka, Sho, Ninomiya-Tsuji, Jun, Takaesu, Giichi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-04-2014; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Binding; Binding proteins; Biology and Life Sciences; Bone marrow; Cell activation; Cell death; Cell Death - drug effects; Cell Death - immunology; Cell survival; Cell Survival - genetics; Chemical properties; Clonal deletion; Experiments; Gene Deletion; Genetic aspects; GTPase-Activating Proteins - antagonists & inhibitors; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Homeostasis; Immunity; Inflammation; Kinases; Lipopolysaccharides; Lipopolysaccharides - immunology; Macrophage Activation - genetics; Macrophage Activation - immunology; Macrophages; Macrophages - immunology; Macrophages - metabolism; MAP Kinase Kinase Kinases - genetics; Mice; Mice, Knockout; Microorganisms; Morphogenesis; Mortality; Peritoneum; Physiological aspects; Protein kinases; Proteins; Research and Analysis Methods; Survival; TAK1 protein; Toxicology; Tumor necrosis factor-TNF; Viability; Japan; North Carolina; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094982

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.