In a recent publication in Nature,Kelepouras et al.identified a novel necroptosis pathway in which activation of stimulator of interferon genes(STING)triggers Z-DNA binding protein 1(ZBP1)-mediated cell death,independ...In a recent publication in Nature,Kelepouras et al.identified a novel necroptosis pathway in which activation of stimulator of interferon genes(STING)triggers Z-DNA binding protein 1(ZBP1)-mediated cell death,independent of canonical tumor necrosis factor receptor 1(TNFR1)and Fas-associated death domain protein(FADD)signaling(Fig.1).These findings provide a transformative therapeutic paradigm by positioning the STINGZBP1 necroptosis axis as a pharmacologically actionable target,offering a mechanism-based strategy to treat STING-associated vasculopathy with onset in infancy(SAVI)and related interferonopathies.展开更多
Gain-of-function mutations in the STING-encoding gene TMEM173 are central to the pathology of the autoinflammatory disorder STING-associated vasculopathy with onset in infancy(SAVI).Furthermore,excessive activity of t...Gain-of-function mutations in the STING-encoding gene TMEM173 are central to the pathology of the autoinflammatory disorder STING-associated vasculopathy with onset in infancy(SAVI).Furthermore,excessive activity of the STING signaling pathway is associated with autoinflammatory diseases,including systemic lupus erythematosus and Aicardi–Goutières syndrome(AGS).Two independent studies recently identified pharmacological inhibitors of STING.Strikingly,both types of compounds are reactive nitrocontaining electrophiles that target STING palmitoylation,a posttranslational modification necessary for STING signaling.As a consequence,the activation of downstream signaling molecules and the induction of type I interferons were inhibited.The compounds were effective at ameliorating inflammation in a mouse model of AGS and in blocking the production of type I interferons in primary fibroblasts from SAVI patients.This mini-review focuses on the roles of palmitoylation in STING activation and signaling and as a pharmaceutical target for drug development.展开更多
Background The role of type I interferon(IFN-I)signaling in systemic lupus erythematosus(SLE)has been well established.However,unanswered questions remain regarding the applicability of these findings to pediatric-ons...Background The role of type I interferon(IFN-I)signaling in systemic lupus erythematosus(SLE)has been well established.However,unanswered questions remain regarding the applicability of these findings to pediatric-onset SLE.The aim of this review is to provide an overview of the novel discoveries on IFN-I signaling in pediatric-onset SLE.Data sources A literature search was conducted in the PubMed database using the following keywords:“pediatric systemic lupus erythematosus”and“type I interferon”.Results IFN-I signaling is increased in pediatric SLE,largely due to the presence of plasmacytoid dendritic cells and pathways such as cyclic GMP-AMP synthase–stimulator of interferon genes–TANK-binding kinase 1 and Toll-like receptor(TLR)4/TLR9.Neutrophil extracellular traps and oxidative DNA damage further stimulate IFN-I production.Genetic variants in IFN-I-related genes,such as IFN-regulatory factor 5 and tyrosine kinase 2,are linked to SLE susceptibility in pediatric patients.In addition,type I interferonopathies,characterized by sustained IFN-I activation,can mimic SLE symptoms and are thus important to distinguish.Studies on interferonopathies also contribute to exploring the pathogenesis of SLE.Measuring IFN-I activation is crucial for SLE diagnosis and stratification.Both IFNstimulated gene expression and serum IFN-α2 levels are common indicators.Flow cytometry markers such as CD169 and galectin-9 are promising alternatives.Anti-IFN therapies,such as sifalimumab and anifrolumab,show promise in adult patients with SLE,but their efficacy in pediatric patients requires further investigation.Janus kinase inhibitors are another treatment option for severe pediatric SLE patients.Conclusions This review presents an overview of the IFN-I pathway in pediatric SLE.Understanding the intricate relationship between IFN-I and pediatric SLE may help to identify potential diagnostic markers and targeted therapies,paving the way for improved patient care and outcomes.展开更多
基金supported by the National Natural Science Foundation of China(32525002,82573201 and 32200575).
文摘In a recent publication in Nature,Kelepouras et al.identified a novel necroptosis pathway in which activation of stimulator of interferon genes(STING)triggers Z-DNA binding protein 1(ZBP1)-mediated cell death,independent of canonical tumor necrosis factor receptor 1(TNFR1)and Fas-associated death domain protein(FADD)signaling(Fig.1).These findings provide a transformative therapeutic paradigm by positioning the STINGZBP1 necroptosis axis as a pharmacologically actionable target,offering a mechanism-based strategy to treat STING-associated vasculopathy with onset in infancy(SAVI)and related interferonopathies.
文摘Gain-of-function mutations in the STING-encoding gene TMEM173 are central to the pathology of the autoinflammatory disorder STING-associated vasculopathy with onset in infancy(SAVI).Furthermore,excessive activity of the STING signaling pathway is associated with autoinflammatory diseases,including systemic lupus erythematosus and Aicardi–Goutières syndrome(AGS).Two independent studies recently identified pharmacological inhibitors of STING.Strikingly,both types of compounds are reactive nitrocontaining electrophiles that target STING palmitoylation,a posttranslational modification necessary for STING signaling.As a consequence,the activation of downstream signaling molecules and the induction of type I interferons were inhibited.The compounds were effective at ameliorating inflammation in a mouse model of AGS and in blocking the production of type I interferons in primary fibroblasts from SAVI patients.This mini-review focuses on the roles of palmitoylation in STING activation and signaling and as a pharmaceutical target for drug development.
基金supported by National Key Research and Development Program of China(2021YFC2702005)National High level Hospital Clinical Research Foundation(2022-PUMCH-B-079).
文摘Background The role of type I interferon(IFN-I)signaling in systemic lupus erythematosus(SLE)has been well established.However,unanswered questions remain regarding the applicability of these findings to pediatric-onset SLE.The aim of this review is to provide an overview of the novel discoveries on IFN-I signaling in pediatric-onset SLE.Data sources A literature search was conducted in the PubMed database using the following keywords:“pediatric systemic lupus erythematosus”and“type I interferon”.Results IFN-I signaling is increased in pediatric SLE,largely due to the presence of plasmacytoid dendritic cells and pathways such as cyclic GMP-AMP synthase–stimulator of interferon genes–TANK-binding kinase 1 and Toll-like receptor(TLR)4/TLR9.Neutrophil extracellular traps and oxidative DNA damage further stimulate IFN-I production.Genetic variants in IFN-I-related genes,such as IFN-regulatory factor 5 and tyrosine kinase 2,are linked to SLE susceptibility in pediatric patients.In addition,type I interferonopathies,characterized by sustained IFN-I activation,can mimic SLE symptoms and are thus important to distinguish.Studies on interferonopathies also contribute to exploring the pathogenesis of SLE.Measuring IFN-I activation is crucial for SLE diagnosis and stratification.Both IFNstimulated gene expression and serum IFN-α2 levels are common indicators.Flow cytometry markers such as CD169 and galectin-9 are promising alternatives.Anti-IFN therapies,such as sifalimumab and anifrolumab,show promise in adult patients with SLE,but their efficacy in pediatric patients requires further investigation.Janus kinase inhibitors are another treatment option for severe pediatric SLE patients.Conclusions This review presents an overview of the IFN-I pathway in pediatric SLE.Understanding the intricate relationship between IFN-I and pediatric SLE may help to identify potential diagnostic markers and targeted therapies,paving the way for improved patient care and outcomes.
