title: Activated macrophage survival is coordinated by TAK1 binding proteins.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: September R
authors.initials: SR
authors.lastname: Mihaly
authors.affiliation: Department of Biological Sciences, Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Sho
authors.initials: S
authors.lastname: Morioka
authors.affiliation: Department of Biological Sciences, Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
authors.affiliation: 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.
authors.forename: Giichi
authors.initials: G
authors.lastname: Takaesu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D008070:Lipopolysaccharides / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D008262:Macrophage Activation / Q000235:genetics* / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7; C490620:Ralbp1 protein, mouse; C531463:Tab1 protein, mouse; C498761:Tab2 protein, mouse
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