Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritisOAMEDLINE
Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that genetics also shape the gut microbiota.It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to CIA.Here,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched B.fragilis than DBA/1J mice and RA patients.Transplantation of B.fragilis prevents CIA in DBA/1J mice.We identify that B.fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate.Fibroblast-like synoviocytes(FLSs)in RA are activated to undergo tumor-like transformation.Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of RA-FLSs.We treat CIA mice with propionate and show that propionate attenuates CIA.Moreover,a combination of propionate with anti-TNF etanercept synergistically relieves CIA.These results suggest that B.fragilis or propionate could be an alternative or complementary approach to the current therapies.
Hongzhen Chen;Xuekun Fu;Xiaohao Wu;Junyi Zhao;Fang Qiu;Zhenghong Wang;Zhuqian Wang;Xinxin Chen;Duoli Xie;Jie Huang;Junyu Fan;Xu Yang;Yi Song;Jie Li;Dongyi He;Guozhi Xiao;Aiping Lu;Chao Liang;
Department of Systems Biology,School of Life Sciences,Southern University of Science and Technology,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Shenzhen 518055,ChinaDepartment of Systems Biology,School of Life Sciences,Southern University of Science and Technology,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Shenzhen 518055,China Institute of Integrated Bioinfomedicine and Translational Science(IBTS),School of Chinese Medicine,Hong Kong Baptist University,Hong Kong SAR 999077,ChinaDepartment of Biochemistry,School of Medicine,Southern University of Science and Technology,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Shenzhen 518055,China Division of Immunology and Rheumatology,Stanford University,Stanford,CA 94305,USA VA Palo Alto Health Care System,Palo Alto,CA 94304,USAInstitute of Plant and Food Science,Department of Biology,Southern University of Science and Technology,Shenzhen 518055,ChinaDepartment of Rheumatology,Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai,ChinaDepartment of Computational Biology,St.Jude Children’s Research Hospital,Memphis,TN,USADepartment of Laboratory Medicine,Peking University Shenzhen Hospital,Shenzhen,ChinaDepartment of Biochemistry,School of Medicine,Southern University of Science and Technology,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Shenzhen 518055,ChinaInstitute of Integrated Bioinfomedicine and Translational Science(IBTS),School of Chinese Medicine,Hong Kong Baptist University,Hong Kong SAR 999077,China Guangdong-Hong Kong-Macao Joint Lab on Chinese Medicine and Immune Disease Research,Guangzhou 510006,China Shanghai University of Traditional Chinese Medicine,Shanghai 200032,ChinaDepartment of Systems Biology,School of Life Sciences,Southern University of Science and Technology,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Shenzhen 518055,China Institute of Integrated Bioinfomedicine and Translational Science(IBTS),School of Chinese Medicine,Hong Kong Baptist University,Hong Kong SAR 999077,China State Key Laboratory of Proteomics,National Center for Protein Sciences(Beijing),Beijing Institute of Lifeomics,100850 Beijing,China
临床医学
HDAC3cytesinterferon
《Bone Research》 2024 (002)
P.421-437 / 17
supported by the National Natural Science Foundation Council of China(82172386 and 81922081 to C.L.,82100943 to X.F.,82104216 to J.L.,and 82230081,82250710175 and 8226116039 to G.X.);the Department of Education of Guangdong Province(2021KTSCX104 to C.L.);the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong Kong-Macao Joint Lab)(2020B1212030006 to A.L.);the Guangdong Provincial Science and Technology Innovation Council Grant(2017B030301018 to G.X.);the Guangdong Basic and Applied Basic Research Foundation(2022A1515012164 to C.L.,and 2023A1515012000 to X.F.);the Science,Technology and Innovation Commission of Shenzhen(JCYJ20210324104201005 to C.L.,JCYJ20220530115006014 to X.F.,JCYJ20230807095118035 to J.L.,and JCYJ20220818100617036 to G.X.);the Hong Kong General Research Fund(12102722 to A.L.);the Hong Kong RGC Themebased Research Scheme(T12-201/20-R to A.L.).
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