Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis.Moreover,although previous studies have reported that the proviral integration of Mo...Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis.Moreover,although previous studies have reported that the proviral integration of Moloney virus 2(Pim2)kinase is involved in various cancers through the mediation of aerobic glycolysis in cancer cells,its role in inflammatory arthritis remains unclear.In this study,we demonstrated that multiple metabolic enzymes are activated upon Pim2 upregulation during M1 macrophage polarization.Specifically,Pim2 directly phosphorylates PGK1-S203,PDHA1-S300,and PFKFB2-S466,thereby promoting glycolytic reprogramming.Pim2 expression was elevated in macrophages from patients with inflammatory arthritis and collageninduced arthritis(CIA)model mice.Conditional knockout of Pim2 in macrophages or administration of the Pim2 inhibitor HJ-PI01 attenuated arthritis development by inhibiting M1 macrophage polarization.Through molecular docking and dynamic simulation,bexarotene was identified as an inhibitor of Pim2 that inhibits glycolysis and downstream M1 macrophage polarization,thereby mitigating the progression of inflammatory arthritis.For targeted treatment,neutrophil membrane-coated bexarotene(Bex)-loaded PLGA-based nanoparticles(NM@NP-Bex)were developed to slow the progression of inflammatory arthritis by suppressing the polarization of M1 macrophages,and these nanoparticles(NPs)exhibited superior therapeutic effects with fewer side effects.Taken together,the results of our study demonstrated that targeting Pim2 inhibition could effectively alleviate inflammatory arthritis via glycolysis inhibition and reversal of the M1/M2 macrophage imbalance.NM@NPs loaded with bexarotene could represent a promising targeted strategy for the treatment of inflammatory arthritis.展开更多
Embryonic stem cells （ESCs） can undergo unlimited self-renewal and maintain pluripotency to differen- tiate into any cell type of the three germ layers. Extensive studies have shown ESC identity is regulated by tran...Embryonic stem cells （ESCs） can undergo unlimited self-renewal and maintain pluripotency to differen- tiate into any cell type of the three germ layers. Extensive studies have shown ESC identity is regulated by transcription factors, epigenetic regulators and multiple signal transduction pathways. However, the kinase regulation of pluripotency is not well understood. Here we show that the serine/threonine kinase PlM2, which is highly expressed in ESCs but not in somatic cells, functions as a crucial stemness regulator in ESCs. Knockout of Pim2 inhibits the self-renewal and differentiation capability of ESCs. Mechanistic studies identified that PIM2 can directly phosphorylate 4E-BP1, leading to release of elF4E which facili- tates the translation of pluripotent genes in ESCs. Our study highlights a novel kinase cascade pathway for ESC identity maintenance.展开更多
Recently, apoptosis has been considered to be an important regulator for allograft survival. The serine/threonine kinase Pim2 has been implicated in many apoptotic pathways. In a previous study, we found that pim2was ...Recently, apoptosis has been considered to be an important regulator for allograft survival. The serine/threonine kinase Pim2 has been implicated in many apoptotic pathways. In a previous study, we found that pim2was highly expressed in CD4＋ T cells in an allograft model. Here, we further investigated the effects of Pim2 on allograft survival and the underlying mechanisms associated with apoptosis. The results showed that pim2 was overexpressed in grafts and spleens, particularly in spleen CD4＋ T cells when acute allorejection occurred, and correlated positively with the extent of rejection. In T cells from the spleens of naive BALB/c mice treated with 5 pM 4a （a specific inhibitor of Pim2） for 24 h, the apoptosis rate increased and the phosphorylation of BAD was decreased. Furthermore, adoptive transfer of CD4＋ T cells treated with 4a in vitroto allografted severe combined immunodeficiency （SCID） mice effectively prolonged allograft survival from 19.5± 1.7 days to 31 ±2.3 days. Moreover, the results demonstrated that the CD4＋CD25- effector T-cell subset was the predominate expresser of the pim2 gene as compared with the CD4＋CD25＋ regulatory T （Treg） cell subset. AIIoantigen-induced CD4＋CD25＋ T cells displayed less Foxp3 expression and a low suppression of apoptosis compared with effector CD4＋CD25- T cells treated with 4a. Collectively, these data revealed that Pim2 facilitated allograft rejection primarily by modulating the apoptosis of effector T cells and the function of Treg cells. These data suggested that Pim2 may be an important target for in vivoanti-rejection therapies and for the ex vivoexpansion of CD4＋CD25＋ T cells.展开更多
基金supported by the National Natural Science Foundation of China(No.82172385 to HS)National Natural Science Foundation of China(No.82172349 to YW)+4 种基金Guangdong Provincial Clinical Research Center for Orthopedic Diseases(No.2023B110001 to HS)Futian Healthcare Research Project(No.FTWS2022020 to JL)Futian Healthcare Research Project(No.FTWS2023058 to JL)Guangdong Natural Science Foundation(No.2023A1515010531 to JL)Shenzhen Science and Technology Program(No.KCXFZ20230731092959001 to PW).
文摘Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis.Moreover,although previous studies have reported that the proviral integration of Moloney virus 2(Pim2)kinase is involved in various cancers through the mediation of aerobic glycolysis in cancer cells,its role in inflammatory arthritis remains unclear.In this study,we demonstrated that multiple metabolic enzymes are activated upon Pim2 upregulation during M1 macrophage polarization.Specifically,Pim2 directly phosphorylates PGK1-S203,PDHA1-S300,and PFKFB2-S466,thereby promoting glycolytic reprogramming.Pim2 expression was elevated in macrophages from patients with inflammatory arthritis and collageninduced arthritis(CIA)model mice.Conditional knockout of Pim2 in macrophages or administration of the Pim2 inhibitor HJ-PI01 attenuated arthritis development by inhibiting M1 macrophage polarization.Through molecular docking and dynamic simulation,bexarotene was identified as an inhibitor of Pim2 that inhibits glycolysis and downstream M1 macrophage polarization,thereby mitigating the progression of inflammatory arthritis.For targeted treatment,neutrophil membrane-coated bexarotene(Bex)-loaded PLGA-based nanoparticles(NM@NP-Bex)were developed to slow the progression of inflammatory arthritis by suppressing the polarization of M1 macrophages,and these nanoparticles(NPs)exhibited superior therapeutic effects with fewer side effects.Taken together,the results of our study demonstrated that targeting Pim2 inhibition could effectively alleviate inflammatory arthritis via glycolysis inhibition and reversal of the M1/M2 macrophage imbalance.NM@NPs loaded with bexarotene could represent a promising targeted strategy for the treatment of inflammatory arthritis.
基金supported by the National Basic Research Program of China (2013CB966901)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01040108)The National Thousand of Talents Program to T.Z., and the National Natural Science Foundation of China (31570995, 31621004) to T.Z. and (31400831) to J.C.
文摘Embryonic stem cells （ESCs） can undergo unlimited self-renewal and maintain pluripotency to differen- tiate into any cell type of the three germ layers. Extensive studies have shown ESC identity is regulated by transcription factors, epigenetic regulators and multiple signal transduction pathways. However, the kinase regulation of pluripotency is not well understood. Here we show that the serine/threonine kinase PlM2, which is highly expressed in ESCs but not in somatic cells, functions as a crucial stemness regulator in ESCs. Knockout of Pim2 inhibits the self-renewal and differentiation capability of ESCs. Mechanistic studies identified that PIM2 can directly phosphorylate 4E-BP1, leading to release of elF4E which facili- tates the translation of pluripotent genes in ESCs. Our study highlights a novel kinase cascade pathway for ESC identity maintenance.
基金This work was supported by grants from the National Natural Science Foundation of China （No. 81071172, G. Hou） and the Natural Science Foundation of Shandong Province （No. ZR2010CM025, G. Hou）.
文摘Recently, apoptosis has been considered to be an important regulator for allograft survival. The serine/threonine kinase Pim2 has been implicated in many apoptotic pathways. In a previous study, we found that pim2was highly expressed in CD4＋ T cells in an allograft model. Here, we further investigated the effects of Pim2 on allograft survival and the underlying mechanisms associated with apoptosis. The results showed that pim2 was overexpressed in grafts and spleens, particularly in spleen CD4＋ T cells when acute allorejection occurred, and correlated positively with the extent of rejection. In T cells from the spleens of naive BALB/c mice treated with 5 pM 4a （a specific inhibitor of Pim2） for 24 h, the apoptosis rate increased and the phosphorylation of BAD was decreased. Furthermore, adoptive transfer of CD4＋ T cells treated with 4a in vitroto allografted severe combined immunodeficiency （SCID） mice effectively prolonged allograft survival from 19.5± 1.7 days to 31 ±2.3 days. Moreover, the results demonstrated that the CD4＋CD25- effector T-cell subset was the predominate expresser of the pim2 gene as compared with the CD4＋CD25＋ regulatory T （Treg） cell subset. AIIoantigen-induced CD4＋CD25＋ T cells displayed less Foxp3 expression and a low suppression of apoptosis compared with effector CD4＋CD25- T cells treated with 4a. Collectively, these data revealed that Pim2 facilitated allograft rejection primarily by modulating the apoptosis of effector T cells and the function of Treg cells. These data suggested that Pim2 may be an important target for in vivoanti-rejection therapies and for the ex vivoexpansion of CD4＋CD25＋ T cells.
