Cell metabolism is an indispensable biochemical process that provides the basic energy and materials necessary for normal cell function.Accumulating evidence implicates abnormal metabolism of T cells as playing a crit...Cell metabolism is an indispensable biochemical process that provides the basic energy and materials necessary for normal cell function.Accumulating evidence implicates abnormal metabolism of T cells as playing a critical role in the pathogenesis of rheumatoid arthritis(RA).The deacetylase SIRT3 has been shown to directly regulate energy metabolism in nonimmune cells.However,the role of SIRT3 in T cells and whether it participates in RA process remain unclear.In this study,we demonstrated that T-cell glycolysis was inhibited after SIRT3 deficiency.Compared to wild-type mice,SIRT3 knockout mice exhibited more severe arthritis,cartilage erosion,and inflammation after immunization with antigen-induced arthritis(AIA).It is interesting to note that SIRT3 deficiency reduced the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3),a regulatory and rate-limiting enzyme in glycolysis.Overexpression of PFKFB3 was shown to restore the impaired ATP production caused by SIRT3 deficiency in T cells,and protects T cells from apoptosis.In summary,SIRT3 plays an important role in the regulation of T-cell metabolism in the pathogenesis of RA.SIRT3 deficiency decreases glycolysis,reduces ATP production,induces apoptosis in CD4+T cells,and further promotes AIA in mice.展开更多
基金supported by grants from the National Key R&D Program of China(2022YFC3602000,2023YFC3403300)National High Level Hospital Clinical Research Funding(BJ-2022-116,BJ-2023-084,BJ-2024-141,BJ-2023-119,BJ-2024-243)+6 种基金National Natural Science Foundation of China(82230060,81801627,32141004,82100564,8210035244,92149305,82225007,82030017,and 82171798,32430036,32441093)Beijing Research Ward Excellence Program(BRWEP2024W234050100)Chinese Academy of Medical Science Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-017,2021-I2M-1040,2021-I2M-1-047,2021-I2M-1-016,2021-I2M-1-026,and 2022-I2M-2-002)National High Level Hospital Clinical Research Funding of Peking Union Medical College Hospital(2023PUMCH-F-004,2022-PUMCH-A-108,Young Reserve Talents of Peking Union Medical College Hospital(UHB12041)the Fundamental Research Funds for the Central Universities(3332018026)the fellowship of China Postdoctoral Science Foundation(2021T140069)Dongcheng District Outstanding Talent Nurturing Program(2023-dchrcpyzz-30)。
文摘Cell metabolism is an indispensable biochemical process that provides the basic energy and materials necessary for normal cell function.Accumulating evidence implicates abnormal metabolism of T cells as playing a critical role in the pathogenesis of rheumatoid arthritis(RA).The deacetylase SIRT3 has been shown to directly regulate energy metabolism in nonimmune cells.However,the role of SIRT3 in T cells and whether it participates in RA process remain unclear.In this study,we demonstrated that T-cell glycolysis was inhibited after SIRT3 deficiency.Compared to wild-type mice,SIRT3 knockout mice exhibited more severe arthritis,cartilage erosion,and inflammation after immunization with antigen-induced arthritis(AIA).It is interesting to note that SIRT3 deficiency reduced the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3),a regulatory and rate-limiting enzyme in glycolysis.Overexpression of PFKFB3 was shown to restore the impaired ATP production caused by SIRT3 deficiency in T cells,and protects T cells from apoptosis.In summary,SIRT3 plays an important role in the regulation of T-cell metabolism in the pathogenesis of RA.SIRT3 deficiency decreases glycolysis,reduces ATP production,induces apoptosis in CD4+T cells,and further promotes AIA in mice.
