start-ver=1.4 cd-journal=joma no-vol=292 cd-vols= no-issue=20 article-no= start-page=8436 end-page=8446 dt-received= dt-revised= dt-accepted= dt-pub-year=2017 dt-pub=201705 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity en-subtitle= kn-subtitle= en-abstract= kn-abstract= Metformin is the first-line drug in the treatment of type 2 diabetes. In addition to its hypoglycemic effect, metformin has an anti-inflammatory function, but the precise mechanism promoting this activity remains unclear. High mobility group box 1 (HMGB1) is an alarmin that is released from necrotic cells and induces inflammatory responses by its cytokine-like activity and is, therefore, a target of anti-inflammatory therapies. Here we identified HMGB1 as a novel metformin-binding protein by affinity purification using a biotinylated metformin analogue. Metformin directly bound to the C-terminal acidic tail of HMGB1. Both in vitro and in vivo, metformin inhibited inflammatory responses induced by full-length HMGB1 but not by HMGB1 lacking the acidic tail. In an acetaminophen-induced acute liver injury model in which HMGB1 released from injured cells exacerbates the initial injury, metformin effectively reduced liver injury and had no additional inhibitory effects when the extracellular HMGB1 was blocked by anti-HMGB1-neutralizing antibody. In summary, we report for the first time that metformin suppresses inflammation by inhibiting the extracellular activity of HMGB1. Because HMGB1 plays a major role in inflammation, our results suggest possible new ways to manage HMGB1-induced inflammation. en-copyright= kn-copyright= en-aut-name=HoriuchiTakahiro en-aut-sei=Horiuchi en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SakataNatsumi en-aut-sei=Sakata en-aut-mei=Natsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NarumiYoshihiro en-aut-sei=Narumi en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KimuraTomohiro en-aut-sei=Kimura en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HayashiTakashi en-aut-sei=Hayashi en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NaganoKeisuke en-aut-sei=Nagano en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=LiuKeyue en-aut-sei=Liu en-aut-mei=Keyue kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NishiboriMasahiro en-aut-sei=Nishibori en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TsukitaSohei en-aut-sei=Tsukita en-aut-mei=Sohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YamadaTetsuya en-aut-sei=Yamada en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KatagiriHideki en-aut-sei=Katagiri en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ShirakawaRyutaro en-aut-sei=Shirakawa en-aut-mei=Ryutaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=HoriuchiHisanori en-aut-sei=Horiuchi en-aut-mei=Hisanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University kn-affil= affil-num=2 en-affil=Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University kn-affil= affil-num=3 en-affil=Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University kn-affil= affil-num=4 en-affil=Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University kn-affil= affil-num=5 en-affil= Biomedical Technology Research Center, Tokushima Research Institute kn-affil= affil-num=6 en-affil=First Institute of New Drug Discovery, Otsuka Pharmaceutical Co kn-affil= affil-num=7 en-affil=Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine kn-affil= affil-num=10 en-affil=Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine kn-affil= affil-num=11 en-affil=Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine kn-affil= affil-num=12 en-affil=Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University kn-affil= affil-num=13 en-affil=Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University kn-affil= en-keyword=cytokine kn-keyword=cytokine en-keyword=inflammation kn-keyword=inflammation en-keyword=liver injury kn-keyword=liver injury en-keyword=metformin kn-keyword=metformin en-keyword=p38 MAPK kn-keyword=p38 MAPK END