Immunometabolism plays a fundamental role in health and diseases and involves multiple genes and signals.Aconitate decarboxylase 1(ACOD1;also known as IRG1)is emerging as a regulator of immunometabolism in inflammatio...Immunometabolism plays a fundamental role in health and diseases and involves multiple genes and signals.Aconitate decarboxylase 1(ACOD1;also known as IRG1)is emerging as a regulator of immunometabolism in inflammation and infection.Upregulation of ACOD1 expression occurs in activated immune cells(e.g.,macrophages and monocytes)in response to pathogen infection(e.g.,bacteria and viruses),pathogen-associated molecular pattern molecules(e.g.,LPS),cytokines(e.g.,TNF and IFNs),and damage-associated molecular patterns(e.g.,monosodium urate).Mechanistically,several immune receptors(e.g.,TLRs and IFNAR),adapter proteins(e.g.,MYD88),ubiquitin ligases(e.g.,A20),and transcription factors(e.g.,NF-κB,IRFs,and STATs)form complex signal transduction networks to control ACOD1 expression in a context-dependent manner.Functionally,ACOD1 mediates itaconate production,oxidative stress,and antigen processing and plays dual roles in immunity and diseases.On the one hand,activation of the ACOD1 pathway may limit pathogen infection and promote embryo implantation.On the other hand,abnormal ACOD1 expression can lead to tumor progression,neurodegenerative disease,and immune paralysis.Further understanding of the function and regulation of ACOD1 is important for the application of ACOD1-based therapeutic strategies in disease.展开更多
Immunometabolism is a dynamic process involving the interplay of metabolism and immune response in health and diseases.Increasing evidence suggests that impaired immunometabolism contributes to infectious and inflamma...Immunometabolism is a dynamic process involving the interplay of metabolism and immune response in health and diseases.Increasing evidence suggests that impaired immunometabolism contributes to infectious and inflammatory diseases.In particular,the mitochondrial enzyme aconitate decarboxylase 1(ACOD1,best known as immunoresponsive gene 1[IRG1])is upregulated under various inflammatory conditions and serves as a pivotal regulator of immunometabolism involved in itaconate production,macrophage polarization,inflammasome activation,and oxidative stress.Consequently,the activation of the ACOD1 pathway is implicated in regulating the pathogenic process of sepsis and septic shock,which are part of a clinical syndrome of life-threatening organ failure caused by a dysregulated host response to pathogen infection.In this review,we discuss the latest research advances in ACOD1 expression and function,with particular attention to how the ACOD1-itaconate pathway affects infection and sterile inflammation diseases.These new insights may give us a deeper understanding of the role of immunometabolism in innate immunity.展开更多
Background and aims:Methane has shown protective effects against ischemia and reperfusion injury(IRI)in the liver,but the mechanism underlying these beneficial effects is unclear.To investigate the hypothesis that ita...Background and aims:Methane has shown protective effects against ischemia and reperfusion injury(IRI)in the liver,but the mechanism underlying these beneficial effects is unclear.To investigate the hypothesis that itaconate facilitates in methane-induced Nrf2 pathway activation to mitigate liver IRI.Methods:An oxygen and glucose derivation(OGD)model using RAW 264.7 cells and a liver IRI model in mice were established.Methane's beneficial effects were assessed through hematoxylin and eosin(HE)staining,Suzuki's score,serum alanine transferase level,superoxide dismutase(SOD)level,malondialdehyde(MDA)level,and cell viability.The relative expression levels of Nrf2,its downstream molecules and some inflammatory factors were detected via western blotting.Itaconate levels were analyzed using liquid chromatography.RAW 264.7 cells were transfected with short hairpin RNA targeting mouse aconitate decarboxylase 1(Acod1)mRNA for itaconate downregulation.Results:Methane significantly alleviated liver IRI,as shown by the significant reduction in Suzuki's scores and alanine transferase(ALT)levels in vivo.Methane treatment significantly increased MTT and SOD levels and decreased MDA levels in the OGD injury model in vitro.Methane also increased the total and nuclear Nrf2 expression levels,activated downstream molecules including heme oxygenase-1(HO-1),NQO1 and affected the production of inflammatory cytokines such as IL-10,IL-1β,and IL-12.Itaconate levels were significantly elevated after methane treatment compared with the OGD injury group.The protective effects of methane were abolished after itaconate downregulation through Acod1 knockdown.Conclusions:Methane alleviates liver IRI through itaconate/Nrf2 pathway activation,with itaconate being critical for methane's beneficial effects.展开更多
文摘Immunometabolism plays a fundamental role in health and diseases and involves multiple genes and signals.Aconitate decarboxylase 1(ACOD1;also known as IRG1)is emerging as a regulator of immunometabolism in inflammation and infection.Upregulation of ACOD1 expression occurs in activated immune cells(e.g.,macrophages and monocytes)in response to pathogen infection(e.g.,bacteria and viruses),pathogen-associated molecular pattern molecules(e.g.,LPS),cytokines(e.g.,TNF and IFNs),and damage-associated molecular patterns(e.g.,monosodium urate).Mechanistically,several immune receptors(e.g.,TLRs and IFNAR),adapter proteins(e.g.,MYD88),ubiquitin ligases(e.g.,A20),and transcription factors(e.g.,NF-κB,IRFs,and STATs)form complex signal transduction networks to control ACOD1 expression in a context-dependent manner.Functionally,ACOD1 mediates itaconate production,oxidative stress,and antigen processing and plays dual roles in immunity and diseases.On the one hand,activation of the ACOD1 pathway may limit pathogen infection and promote embryo implantation.On the other hand,abnormal ACOD1 expression can lead to tumor progression,neurodegenerative disease,and immune paralysis.Further understanding of the function and regulation of ACOD1 is important for the application of ACOD1-based therapeutic strategies in disease.
文摘Immunometabolism is a dynamic process involving the interplay of metabolism and immune response in health and diseases.Increasing evidence suggests that impaired immunometabolism contributes to infectious and inflammatory diseases.In particular,the mitochondrial enzyme aconitate decarboxylase 1(ACOD1,best known as immunoresponsive gene 1[IRG1])is upregulated under various inflammatory conditions and serves as a pivotal regulator of immunometabolism involved in itaconate production,macrophage polarization,inflammasome activation,and oxidative stress.Consequently,the activation of the ACOD1 pathway is implicated in regulating the pathogenic process of sepsis and septic shock,which are part of a clinical syndrome of life-threatening organ failure caused by a dysregulated host response to pathogen infection.In this review,we discuss the latest research advances in ACOD1 expression and function,with particular attention to how the ACOD1-itaconate pathway affects infection and sterile inflammation diseases.These new insights may give us a deeper understanding of the role of immunometabolism in innate immunity.
基金funded by National Natural Science Foundation of China(82000587,82202382)the Beijing Municipal Natural Science Foundation(7242135)。
文摘Background and aims:Methane has shown protective effects against ischemia and reperfusion injury(IRI)in the liver,but the mechanism underlying these beneficial effects is unclear.To investigate the hypothesis that itaconate facilitates in methane-induced Nrf2 pathway activation to mitigate liver IRI.Methods:An oxygen and glucose derivation(OGD)model using RAW 264.7 cells and a liver IRI model in mice were established.Methane's beneficial effects were assessed through hematoxylin and eosin(HE)staining,Suzuki's score,serum alanine transferase level,superoxide dismutase(SOD)level,malondialdehyde(MDA)level,and cell viability.The relative expression levels of Nrf2,its downstream molecules and some inflammatory factors were detected via western blotting.Itaconate levels were analyzed using liquid chromatography.RAW 264.7 cells were transfected with short hairpin RNA targeting mouse aconitate decarboxylase 1(Acod1)mRNA for itaconate downregulation.Results:Methane significantly alleviated liver IRI,as shown by the significant reduction in Suzuki's scores and alanine transferase(ALT)levels in vivo.Methane treatment significantly increased MTT and SOD levels and decreased MDA levels in the OGD injury model in vitro.Methane also increased the total and nuclear Nrf2 expression levels,activated downstream molecules including heme oxygenase-1(HO-1),NQO1 and affected the production of inflammatory cytokines such as IL-10,IL-1β,and IL-12.Itaconate levels were significantly elevated after methane treatment compared with the OGD injury group.The protective effects of methane were abolished after itaconate downregulation through Acod1 knockdown.Conclusions:Methane alleviates liver IRI through itaconate/Nrf2 pathway activation,with itaconate being critical for methane's beneficial effects.
