title: Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages.
abstract: Macrophages consist of at least two subgroups, M1 and M2 (refs 1-3). Whereas M1 macrophages are proinflammatory and have a central role in host defence against bacterial and viral infections, M2 macrophages are associated with responses to anti-inflammatory reactions, helminth infection, tissue remodelling, fibrosis and tumour progression. Trib1 is an adaptor protein involved in protein degradation by interacting with COP1 ubiquitin ligase. Genome-wide association studies in humans have implicated TRIB1 in lipid metabolism. Here we show that Trib1 is critical for the differentiation of F4/80(+)MR(+) tissue-resident macrophages--that share characteristics with M2 macrophages (which we term M2-like macrophages)--and eosinophils but not for the differentiation of M1 myeloid cells. Trib1 deficiency results in a severe reduction of M2-like macrophages in various organs, including bone marrow, spleen, lung and adipose tissues. Aberrant expression of C/EBPα in Trib1-deficient bone marrow cells is responsible for the defects in macrophage differentiation. Unexpectedly, mice lacking Trib1 in haematopoietic cells show diminished adipose tissue mass accompanied by evidence of increased lipolysis, even when fed a normal diet. Supplementation of M2-like macrophages rescues the pathophysiology, indicating that a lack of these macrophages is the cause of lipolysis. In response to a high-fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance, together with increased proinflammatory cytokine gene induction. Collectively, these results demonstrate that Trib1 is critical for adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue-resident M2-like macrophages.
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kidoya
authors.forename: Hisamichi
authors.initials: H
authors.lastname: Naito
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Takemura
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Eiichi
authors.initials: E
authors.lastname: Morii
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takakura
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D004804:Eosinophils / Q000166:cytology / Q000378:metabolism; D005260:Female; D015228:Hypertriglyceridemia / Q000139:chemically induced / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008060:Lipodystrophy / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008066:Lipolysis; D008168:Lung / Q000166:cytology; D008264:Macrophages / Q000145:classification / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013154:Spleen / Q000166:cytology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D018797:Cell Cycle Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; C474830:TRB3 protein, mouse; C523598:Trib1 protein, mouse; D025801:Ubiquitin; C515847:tribbles 2 protein, mouse; D017346:Protein Serine-Threonine Kinases