Recent advances in stem cell technologies have opened new avenues for the treatment of a number of diseases still lacking effective therapeutic options.Cell transplantation has emerged as among the most promising clin...Recent advances in stem cell technologies have opened new avenues for the treatment of a number of diseases still lacking effective therapeutic options.Cell transplantation has emerged as among the most promising clinical intervention for disorders such as injuries,diabetes,liver diseases, neurodegeneration and heart failure （Lee et al., 2013; Forbes and Rosenthal, 2014; Tabar and Studer, 2014）.展开更多
Uveitis,a vision-threatening inflammatory disease worldwide,is closely related to resident microglia.Retinal microglia are the main immune effector cells with strong plasticity,but their role in uveitis remains unclea...Uveitis,a vision-threatening inflammatory disease worldwide,is closely related to resident microglia.Retinal microglia are the main immune effector cells with strong plasticity,but their role in uveitis remains unclear.N6-methyladenosine(m^(6)A)modification has been proven to be involved in the immune response.Therefore,we in this work aimed to identify the potentially crucial m^(6)A regulators of microglia in uveitis.Through the single-cell sequencing(scRNA-seq)analysis and experimental verification,we found a significant decrease in the expression of fat mass and obesity-associated protein(FTO)in retinal microglia of uveitis mice and human microglia clone 3(HMC3)cells with inflammation.Additionally,FTO knockdown was found to aggravate the secretion of inflammatory factors and the mobility/chemotaxis of microglia.Mechanistically,the RNA-seq data and rescue experiments showed that glypican 4(GPC4)was the target of FTO,which regulated microglial inflammation mediated by the TLR4/NF-κB pathway.Moreover,RNA stability assays indicated that GPC4 upregulation was mainly regulated by the downregulation of the m^(6)A“reader”YTH domain family protein 3(YTHDF3).Finally,the FTO inhibitor FB23-2 further exacerbated experimental autoimmune uveitis(EAU)inflammation by promoting the GPC4/TLR4/NF-κB signaling axis,and this could be attenuated by the TLR4 inhibitor TAK-242.Collectively,a decreased FTO could facilitate microglial inflammation in EAU,suggesting that the restoration or activation of FTO function may be a potential therapeutic strategy for uveitis.展开更多
基金supported by Fondation pour la Recherche Médicale(Equipe FRM),SATT Sud Est-Accelerator of Technology Transfer,Association France Parkinson,Fondation de France(Committee Parkinson),COST Action CM1106
文摘Recent advances in stem cell technologies have opened new avenues for the treatment of a number of diseases still lacking effective therapeutic options.Cell transplantation has emerged as among the most promising clinical intervention for disorders such as injuries,diabetes,liver diseases, neurodegeneration and heart failure （Lee et al., 2013; Forbes and Rosenthal, 2014; Tabar and Studer, 2014）.
基金supported by the National Natural Science Foundation Project of China(No.82070951,82271078 and 81873678)the Innovative Research Group Project of Chongqing Education Commission(China)(No.CXQT19015)+5 种基金the Natural Science Foundation Project of Chongqing,China(No.cstc2019jcyjmsxmx0120)the Innovation Supporting Plan of Overseas Study of Chongqing,China(No.cx2018010)the Chongqing Education Commission(China)(No.KJQN202000406)the National Key Clinical Specialties Construction Program of China,Chongqing Branch of National Clinical Research Center for Ocular Diseasesthe Chongqing Key Laboratory of Ophthalmology(China)(CSTC,No.2008CA5003)Natural Science Foundation Project of Chongqing Medical University(China)(No.W0047).
文摘Uveitis,a vision-threatening inflammatory disease worldwide,is closely related to resident microglia.Retinal microglia are the main immune effector cells with strong plasticity,but their role in uveitis remains unclear.N6-methyladenosine(m^(6)A)modification has been proven to be involved in the immune response.Therefore,we in this work aimed to identify the potentially crucial m^(6)A regulators of microglia in uveitis.Through the single-cell sequencing(scRNA-seq)analysis and experimental verification,we found a significant decrease in the expression of fat mass and obesity-associated protein(FTO)in retinal microglia of uveitis mice and human microglia clone 3(HMC3)cells with inflammation.Additionally,FTO knockdown was found to aggravate the secretion of inflammatory factors and the mobility/chemotaxis of microglia.Mechanistically,the RNA-seq data and rescue experiments showed that glypican 4(GPC4)was the target of FTO,which regulated microglial inflammation mediated by the TLR4/NF-κB pathway.Moreover,RNA stability assays indicated that GPC4 upregulation was mainly regulated by the downregulation of the m^(6)A“reader”YTH domain family protein 3(YTHDF3).Finally,the FTO inhibitor FB23-2 further exacerbated experimental autoimmune uveitis(EAU)inflammation by promoting the GPC4/TLR4/NF-κB signaling axis,and this could be attenuated by the TLR4 inhibitor TAK-242.Collectively,a decreased FTO could facilitate microglial inflammation in EAU,suggesting that the restoration or activation of FTO function may be a potential therapeutic strategy for uveitis.
